Integrated cold therapy and electrical stimulation systems for locating and treating nerves and associated methods

ABSTRACT

The present invention generally relates to improved medical devices, systems, and methods. In many embodiments, devices, systems, and methods for locating and treating a target nerve with integrated cold therapy and electrical stimulation systems are provided. For example, nerve stimulation and cryoneurolysis may be delivered concurrently or alternately with the cryo-stimulation device. In some embodiments, the device may be operated by a single operator or clinician. Accordingly, embodiments of the present disclosure may improve nerve targeting during cryoneurolysis procedures. Improvements in nerve localization and targeting may increase treatment accuracy, physician confidence in needle placement during treatment, and clinical efficacy and safety. In turn, such improvements may decrease overall treatment times, the number of repeat treatments, and the re-treatment rate. Further, additional improvements in nerve localization and targeting may reduce the number of needle insertions, applied treatment cycles, and may also reduce the number of cartridge changes.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/191,660, filed Nov. 15, 2018, which claims the benefit ofU.S. Provisional Application No. 62/586,625, filed Nov. 15, 2017, whichare incorporated by reference herein in their entirety for all purposes.

The present application is related to U.S. Publication No. 2018/0116705filed May 12, 2017, Ser. No. 15/594,238 filed May 12, 2017, entitled“METHODS AND SYSTEMS FOR LOCATING AND TREATING NERVES WITH COLDTHERAPY”, which is assigned to the same assignee as the presentapplication, and the full disclosure of which is incorporated herein byreference in its entirety for all purposes.

BACKGROUND

The present invention generally related to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor locating and treating a nerve with integrated cold therapy andelectrical stimulation systems are provided.

Cryoneurolysis or cryoneuroablation may be used to treat nerves totemporarily stop nerve signaling, typically for a set period of time,and may be followed by a restoration of nerve function. Cryoneurolysiscan be used on motor nerves for various cosmetic applications and/ormedical conditions, including but not limited to: movement disorders,muscle spasms, muscle hyperactivity and/or any condition where reductionin muscle movement is desired. Additionally, Cryoneurolysis may be usedon sensory nerves to provide temporary or permanent pain relief bydegenerating the nerve and providing a peripheral nerve block. WhileCryoneurolysis has many beneficial applications, further improvements inthe methods, devices, and systems may be had.

SUMMARY

The present invention generally relates to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor locating and treating a target nerve with integrated cold therapyand electrical stimulation systems are provided. For example, nervestimulation and cryoneurolysis may be delivered concurrently oralternately with the cryo-stimulation device. Further, in someembodiments, the device may be operated by a single operator orclinician. In yet other embodiments, manufacturability may be improvedor costs decreased. In other embodiments, ease of assembly may also beimproved. Accordingly, such embodiments of the present disclosure mayimprove nerve targeting during cryoneurolysis procedures. Improvementsin nerve localization and targeting may increase treatment accuracy andphysician confidence in needle placement during treatment. In turn, suchimprovements may decrease overall treatment times, the number of repeattreatments, and the re-treatment rate. Further, additional improvementsin nerve localization and targeting may reduce the number of needleinsertions, applied treatment cycles, and may also reduce the number ofcartridge changes (when replaceable refrigerant cartridges are used).Thus, embodiments of the present disclosure may provide one or moreadvantages for cryoneurolysis by improving localization and treatment oftarget nerves. Hence, some aspects of the present disclosure providemethods, devices, and systems for localizing, targeting, and treating anerve with integrated cold therapy and electrical stimulation systems.

In some embodiments, a cryo-stimulation treatment device may be providedthat includes a needle assembly having a proximal portion and a distalportion. The needle assembly may be configured to produce a cold zonefor cryoneurolysis of a target nerve. The device includes first andsecond electrical contacts coupled to the distal portion of the needleassembly and configured to be electrically coupled to an electricalnerve stimulation generator to provide bipolar stimulation, using eitherbiphasic or monophasic stimulation signals. The electrical nervestimulation generator is configured to generate a first electric fieldabout the first and second electrical contacts for electricallystimulating and locating the target nerve.

In some embodiments, a treatment device includes a handle defined by ahousing coupled to the proximal portion of the needle assembly. Theelectrical nerve stimulation generator may be disposed within the handlehousing. In other embodiments, an external electrical nerve stimulationgenerator is coupled to an electrical port on the handle housing or theneedle assembly. In some aspects, the second electrical contact (e.g.,return electrode) is an anode and the first electrical contact (e.g.,active or stimulating electrode closest to nerve being stimulated) is acathode.

In certain embodiments, the treatment device further includes a thirdelectrical contact spaced apart from the needle assembly and configuredto be electrically coupled to the electrical nerve stimulation generatorand at least one of the first or second electrical contacts to providemonopolar stimulation. The electrical nerve stimulation generator isconfigured to generate a second electric field about the thirdelectrical contact and the at least one of the first or secondelectrical contacts for electrically stimulating and locating the targetnerve. In some embodiments, the third electrical contact serves as areturn electrode and the at least one of the first or second electricalcontacts serves as an active electrode. In some aspects, thirdelectrical contact is configured to be positioned on skin of a patient(e.g., patient's leg or back), a housing of the treatment device, or aheater block of the treatment device.

In some embodiments, the second electric field is generated prior to thefirst electric field. It may be advantageous generate the secondmonopolar electric field initially for gross positioning and then switchto the first bipolar stimulation to fine-tune the positioning of theneedle. In some aspects, the first and second electrical contacts arelocated asymmetrically on the needle assembly. In some embodiments, adistal end of the needle assembly comprises a beveled edge. In someaspects, the first electrical contact extends along the beveled edge. Insome aspects, only a distal tip of the beveled edge is electricallyconductive.

In certain embodiments, a contact surface area of the second electricalcontact is greater than a contact surface area of the first electricalcontact. In some aspects, the first and second electrical contacts faceopposing directions. In some aspects, the first and second electricalcontacts comprise concave-shaped, convex-shaped, or round-shapedelectrodes. In some embodiments, the needle assembly comprises at leastone or more needles and the two or more electrical contracts may resideon or within the same or separate needles. Still further, the electricalcontacts may reside on or within the needle, heater assembly, and/orhousing of the needle assembly and function as either an active orreturn electrode.

In certain embodiments, a cryo-stimulation treatment device is providedthat includes a needle assembly configured to produce a cold zone forcryoneurolysis of a target nerve. The needle assembly includes a firstshaft constructed of electrically conductive material and including anelectrically insulating coating. The first shaft includes a proximalend, a distal end, and length therebetween. The proximal end of thefirst shaft is couplable with an electrical nerve stimulation generatorthat generates an electric field for electrically stimulating andlocating the target nerve. The device further includes a second shaftcomprising a proximal end, a distal end, and a shaft lumen extendingtherebetween. The second shaft further includes a cooling fluid supplylumen extending distally within the shaft lumen to a distal portion ofthe shaft lumen of the second shaft.

In some aspects, the first shaft is retractable relative to the secondshaft. In certain aspects, the distal ends of the first shaft and thesecond shaft form a beveled distal end of the needle.

In further embodiments, the device further includes a third shaft. Thethird shaft includes a proximal end, a distal end, and a shaft lumenextending therebetween. The second shaft and third shaft extend axiallyalong opposing sides of the first shaft. According to certain aspects,the first shaft is retractable relative to the second shaft and thethird shaft.

In yet further embodiments, the device includes a heating element and asensor or heater block may be coupled to the heating element that actsas electrical return during electrical nerve stimulation of the targetnerve. In some embodiments, the device further includes a housing andthe housing acts as electrical return during electrical nervestimulation of the target nerve. In some aspects as discussed herein,the sensor, heater block, or housing may function as either the returnor active electrode.

In some embodiments, a distal end portion of the first shaft isuninsulated by the electrically insulating coating such that theelectric field is generated only about the distal end portion of thefirst shaft to stimulate the target nerve. In certain aspects, only atip of the distal end portion is uninsulated by the electricallyinsulating coating.

In certain embodiments, the device further includes a cooling fluidsource couplable to the cooling fluid supply lumen to direct coolingfluid flow into the second shaft lumen so that liquid from the coolingfluid flow vaporizes within the second shaft lumen to produce the coldzone. In further aspects, the first and second shafts extendcontiguously.

In further embodiments, a cryo-stimulation treatment device is providedthat includes a needle assembly having a proximal portion and a distalportion, the needle assembly configured to produce a cold zone forcryoneurolysis of a target nerve. The device includes a first electricalcontact coupled to the distal portion of the needle assembly and asecond electrical contact positioned on a heater assembly of the needleassembly configured to serve as a return electrode. The first and secondelectrical contacts are configured to be electrically coupled to anelectrical nerve stimulation generator to provide electrical stimulationfor electrically stimulating and locating the target nerve. In someaspects, the heater assembly includes a heater block. In some aspects,the heater electrode may advantageously provide a confirmation signalthat the heater is in contact with the skin surface for patient safetypurposes. For example, the confirmation may comprise an impedancemeasurement that is below 10 K ohms.

In yet other embodiments, a method of treating a nerve is provided thatincludes the steps of: inserting one or more needles of a needleassembly into a tissue of a patient, electrically stimulating the nervewith the needle assembly via bipolar electrical stimulation to localizethe nerve within the tissue, and after localizing of the nerve viabipolar electrical stimulation, delivering cryoneurolysis to the nervewith the needle assembly.

In certain aspects, the method further includes electrically stimulatingthe nerve with the needle assembly via monopolar electrical stimulationprior to electrically stimulating the nerve with the needle assembly viabipolar electrical stimulation to initially localize the nerve withinthe tissue. For example, the method could employ a third electricalcontact acting as a return (or anode) connection located on the skinsurface of the skin. The device would then provide a stimulation signalbetween its active (or cathode) electrode in the needle assembly and theskin electrode to provide monopolar stimulation to allow the user toinitially locate the target nerve for gross positioning. Following this,the user could then switch to a bipolar stimulation mode that wouldbreak the return connection with the skin electrode and provide astimulation signal path between the active electrode and a second returnelectrode located on the same or adjacent needle. This bipolarstimulation would then be used to precisely locate and fine tune needleplacement on the target nerve.

According to other aspects, the method further includes electricallystimulating the nerve with the needle assembly via bipolar electricalstimulation to localize the nerve within the tissue includes generatinga first electric field about asymmetrically located first and secondelectrical contacts coupled to the needle assembly.

DESCRIPTION OF THE DRAWINGS

Further details, aspects and embodiments of the invention will bedescribed by way of example only and with reference to the drawings. Inthe drawings, like reference numbers are used to identify like orfunctionally similar elements. Elements in the figures are illustratedfor simplicity and clarity and have not necessarily been drawn to scale.

FIG. 1A is a perspective view of a self-contained subdermal cryogenicprobe and system, according to some embodiments of the invention;

FIG. 1B is a partially transparent perspective view of theself-contained probe of FIG. 1A, showing internal components of thecryogenic system and schematically illustrating replacement treatmentneedles for use with the disposable probe according to some embodimentsof the invention;

FIG. 2A schematically illustrates exemplary components that may beincluded in the treatment system;

FIG. 2B is a cross-sectional view of the system of FIG. 1A, according tosome embodiments of the invention;

FIGS. 2C and 2D are cross-sectional views showing exemplary operationalconfigurations of a portion of the system of FIG. 2B;

FIGS. 3A-3E illustrate exemplary embodiments of needle probes, accordingto some embodiments of the invention;

FIGS. 4A and 4B illustrate an exemplary system according to someembodiments;

FIG. 5A illustrates an exemplary method of treating a nerve according tosome embodiments;

FIG. 5B illustrates another exemplary method of locating and treating anerve according to some embodiments;

FIG. 6A illustrates an exemplary needle assembly according to someembodiments;

FIG. 6B illustrates a close up view of a needle of the exemplary needleassembly of FIG. 6A according to some embodiments;

FIG. 6C illustrates an exemplary needle configuration according to someembodiments;

FIG. 7 illustrates an exemplary treatment system with a replaceableneedle assembly having an electrical port for coupling with a waveformgenerator of a percutaneous electrical stimulation device according tosome embodiments;

FIG. 8 illustrates the exemplary replaceable needle assembly of FIG. 7according to some embodiments;

FIG. 9 illustrates yet another exemplary treatment system with a handlehaving an electrical port for coupling with a waveform generator of apercutaneous electrical nerve stimulation device according to someembodiments;

FIG. 10 illustrates a view of a proximal end of the exemplary treatmentsystem of FIG. 9 according to some embodiments;

FIG. 11 illustrates yet another exemplary treatment system with a fullyintegrated percutaneous electrical stimulation device according to someembodiments;

FIG. 12 illustrates another exemplary needle assembly according to someembodiments;

FIG. 13 illustrates an exemplary treatment system with an integratedtranscutaneous electrical nerve stimulation probe according to someembodiments;

FIG. 14 illustrates an exemplary operation of the exemplary system ofFIG. 13 according to some embodiments;

FIG. 15A illustrates an exemplary needle assembly of an integrated coldtherapy and electrical stimulation system according to some embodiments;

FIG. 15B illustrates another exemplary needle assembly of an integratedcold therapy and electrical stimulation system according to someembodiments;

FIGS. 16A-16D illustrate other exemplary needle assemblies of anintegrated cold therapy and electrical stimulation system according tosome embodiments;

FIGS. 17A-17C illustrate yet other exemplary needle assemblies of anintegrated cold therapy and electrical stimulation system according tosome embodiments; and

FIG. 18 illustrates an exemplary needle assembly of an integrated coldtherapy and electrical stimulation system according to some embodiments.

DETAILED DESCRIPTION

The present invention provides improved medical devices, systems, andmethods. Embodiments of the invention may treat target tissues disposedat and below the skin, optionally to treat pain associated with asensory nerve. In some embodiments, systems, devices, and methods of thepresent disclosure may utilize an integrated cold therapy and nervestimulation device for localization and treatment of a target nerve.

Embodiments of the invention may utilize a handheld refrigeration systemthat can use a commercially available cartridge of fluid refrigerant.Refrigerants well-suited for use in handheld refrigeration systems mayinclude nitrous oxide and carbon dioxide. These can achieve temperaturesapproaching −90° C.

Sensory nerves and associated tissues may be temporarily impaired usingmoderately cold temperatures of 10° C. to −5° C. without permanentlydisabling the tissue structures. Using an approach similar to thatemployed for identifying structures associated with atrial fibrillationor for peripheral nerve blocks, a needle probe or other treatment devicecan be used to identify a target tissue structure in a diagnostic modewith these moderate temperatures, and the same probe (or a differentprobe) can also be used to provide a longer term or permanent treatment,optionally by treating the target tissue zone and/or inducing apoptosisat temperatures from about −5° C. to about −50° C. In some embodiments,apoptosis may be induced using treatment temperatures from about −1° C.to about −15° C., or from about −1° C. to about −19° C., optionally soas to provide a longer lasting treatment that limits or avoidsinflammation and mobilization of skeletal muscle satellite repair cells.In some embodiments, axonotmesis with Wallerian degeneration of asensory nerve is desired, which may be induced using treatmenttemperatures from about −20° C. to about −100° C. Hence, the duration ofthe treatment efficacy of such subdermal cryogenic treatments may beselected and controlled, with colder temperatures, longer treatmenttimes, and/or larger volumes or selected patterns of target tissuedetermining the longevity of the treatment. Additional description ofcryogenic cooling methods and devices may be found in commonly assignedU.S. Pat. No. 7,713,266 entitled “Subdermal Cryogenic Remodeling ofMuscle, Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”, U.S.Pat. No. 7,850,683 entitled “Subdermal Cryogenic Remodeling of Muscles,Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”, U.S. Pat. No.9,039,688 entitled “Method for Reducing Hyperdynamic Facial Wrinkles”,and U.S. Pat. No. 8,298,216 entitled “Pain Management Using CryogenicRemodeling,” the full disclosures of which are each incorporated byreference herein.

Referring now to FIGS. 1A and 1B, a system for cryogenic remodeling herecomprises a self-contained probe handpiece generally having a proximalend 12 and a distal end 14. A handpiece body or housing 16 has a sizeand ergonomic shape suitable for being grasped and supported in asurgeon's hand or other system operator. As can be seen most clearly inFIG. 1B, a cryogenic cooling fluid supply 18, a supply valve 32 andelectrical power source 20 are found within housing 16, along with acircuit 22S having a processor for controlling cooling applied byself-contained system 10 in response to actuation of an input 24.Alternatively, electrical power can be applied through a cord from aremote power source. Power source 20 may also supply power to anoptional heater element 44 in order to heat the proximal region of probe26 which may thereby help to prevent unwanted skin damage, and atemperature sensor 48 adjacent the proximal region of probe 26 whichhelps monitor probe temperature. Additional details on the heater 44 andtemperature sensor 48 are described in greater detail below. Whenactuated, supply valve 32 controls the flow of cryogenic cooling fluidfrom fluid supply 18. Some embodiments may, at least in part, bemanually activated, such as through the use of a manual supply valveand/or the like, so that processors, electrical power supplies, and thelike may not be required.

Extending distally from distal end 14 of housing 16 may be atissue-penetrating cryogenic cooling probe 26. Probe 26 is thermallycoupled to a cooling fluid path extending from cooling fluid source 18,with the exemplary probe comprising a tubular body receiving at least aportion of the cooling fluid from the cooling fluid source therein. Theprobe 26 may comprise a 30 G needle or smaller gauge (e.g., 27 G) havinga sharpened distal end that is axially sealed. Probe 26 may have anaxial length between distal end 14 of housing 16 and the distal end ofthe needle of between about 0.5 mm and 15 cm. Such needles may comprisea stainless steel tube with an inner diameter of about 0.006 inches andan outer diameter of about 0.012 inches, while alternative probes maycomprise structures having outer diameters (or other lateralcross-sectional dimensions) from about 0.006 inches to about 0.100inches. Generally, needle probe 26 may comprise a 16 G or smallerdiameter needle, often comprising a 20 G needle or smaller, typicallycomprising a 22, 25, 26, 27, 28, 29, or 30 G or smaller diameter needle.

In some embodiments, probe 26 may comprise two or more needles arrangedin a linear array, such as those disclosed in previously incorporatedU.S. Pat. No. 7,850,683. Another exemplary embodiment of a probe havingmultiple needle probe configurations allow the cryogenic treatment to beapplied to a larger or more specific treatment area. Other needleconfigurations that facilitate controlling the depth of needlepenetration and insulated needle embodiments are disclosed in commonlyassigned U.S. Pat. No. 8,409,185 entitled “Replaceable and/or EasilyRemovable Needle Systems for Dermal and Transdermal CryogenicRemodeling,” the entire content of which is incorporated herein byreference. Multiple needle arrays may also be arrayed in alternativeconfigurations such as a triangular or square array.

Arrays may be designed to treat a particular region of tissue, or toprovide a uniform treatment within a particular region, or both. In someembodiments needle 26 may be releasably coupled with body 16 so that itmay be replaced after use with a sharper needle (as indicated by thedotted line) or with a needle having a different configuration. Inexemplary embodiments, the needle may be threaded into the body, pressfit into an aperture in the body or have a quick disconnect such as adetent mechanism for engaging the needle with the body. A quickdisconnect with a check valve may be advantageous since it may permitdecoupling of the needle from the body at any time without excessivecoolant discharge. This can be a useful safety feature in the event thatthe device fails in operation (e.g. valve failure), allowing an operatorto disengage the needle and device from a patient's tissue withoutexposing the patient to coolant as the system depressurizes. Thisfeature may also be advantageous because it allows an operator to easilyexchange a dull needle with a sharp needle in the middle of a treatment.One of skill in the art will appreciate that other coupling mechanismsmay be used.

Addressing some of the components within housing 16, the exemplarycooling fluid supply 18 may comprise a canister, sometimes referred toherein as a cartridge, containing a liquid under pressure, with theliquid preferably having a boiling temperature of less than 37° C. atone atmosphere of pressure. When the fluid is thermally coupled to thetissue-penetrating probe 26, and the probe is positioned within thepatient so that an outer surface of the probe is adjacent to a targettissue, the heat from the target tissue evaporates at least a portion ofthe liquid and the enthalpy of vaporization cools the target tissue. Asupply valve 32 may be disposed along the cooling fluid flow pathbetween canister 18 and probe 26, or along the cooling fluid path afterthe probe so as to limit coolant flow thereby regulating thetemperature, treatment time, rate of temperature change, or othercooling characteristics. The valve will often be powered electricallyvia power source 20, per the direction of processor 22, but may at leastin part be manually powered. The exemplary power source 20 comprises arechargeable or single-use battery. Additional details about valve 32are disclosed below and further disclosure on the power source 20 may befound in commonly assigned Int'l Pub. No. WO 2010/075438 entitled“Integrated Cryosurgical Probe Package with Fluid Reservoir and LimitedElectrical Power Source,” the entire contents of which are incorporatedherein by reference.

The exemplary cooling fluid supply 18 may comprise a single-usecanister. Advantageously, the canister and cooling fluid therein may bestored and/or used at (or even above) room temperature. The canister mayhave a frangible seal or may be refillable, with the exemplary canistercontaining liquid nitrous oxide, N₂O. A variety of alternative coolingfluids might also be used, with exemplary cooling fluids includingfluorocarbon refrigerants and/or carbon dioxide. The quantity of coolingfluid contained by canister 18 will typically be sufficient to treat atleast a significant region of a patient, but will often be less thansufficient to treat two or more patients. An exemplary liquid N₂Ocanister might contain, for example, a quantity in a range from about 1gram to about 40 grams of liquid, more preferably from about 1 gram toabout 35 grams of liquid, and even more preferably from about 7 grams toabout 30 grams of liquid.

Processor or controller 22 will typically comprise a programmableelectronic microprocessor embodying machine readable computer code orprogramming instructions for implementing one or more of the treatmentmethods described herein. The microprocessor will typically include orbe coupled to a memory (such as a non-volatile memory, a flash memory, aread-only memory (“ROM”), a random access memory (“RAM”), or the like)storing the computer code and data to be used thereby, and/or arecording media (including a solid state recording media such as a flashmemory drive; a magnetic recording media such as a hard disk, a floppydisk, or the like; or an optical recording media such as a CD or DVD)may be provided. Suitable interface devices (such as digital-to-analogor analog-to-digital converters, or the like) and input/output devices(such as USB or serial I/O ports, wireless communication cards,graphical display cards, and the like) may also be provided. A widevariety of commercially available or specialized processor structuresmay be used in different embodiments, and suitable processors may makeuse of a wide variety of combinations of hardware and/orhardware/software combinations. For example, processor 22 may beintegrated on a single processor board and may run a single program ormay make use of a plurality of boards running a number of differentprogram modules in a wide variety of alternative distributed dataprocessing or code architectures.

Referring now to FIG. 2A, schematic 11 shows a simplified diagram ofcryogenic cooling fluid flow and control. The flow of cryogenic coolingfluid from fluid supply 18 may be controlled by a supply valve 32.Supply valve 32 may comprise an electrically actuated solenoid valve, amotor actuated valve or the like operating in response to controlsignals from controller 22, and/or may comprise a manual valve.Exemplary supply valves may comprise structures suitable for on/offvalve operation, and may provide venting of the fluid source and/or thecooling fluid path downstream of the valve when cooling flow is haltedso as to limit residual cryogenic fluid vaporization and cooling.Additionally, the valve may be actuated by the controller in order tomodulate coolant flow to provide high rates of cooling in some instanceswhere it is desirable to promote necrosis of tissue such as in malignantlesions and the like or slow cooling which promotes ice formationbetween cells rather than within cells when necrosis is not desired.More complex flow modulating valve structures might also be used inother embodiments. For example, other applicable valve embodiments aredisclosed in previously incorporated U.S. Pat. No. 8,409,185.

Still referring to FIG. 2A, an optional heater (not illustrated) may beused to heat cooling fluid supply 18 so that heated cooling fluid flowsthrough valve 32 and through a lumen 34 of a cooling fluid supply tube36. In some embodiments a safety mechanism can be included so that thecooling supply is not overheated. Examples of such embodiments aredisclosed in commonly assigned International Publication No. WO2010075438, the entirety of which is incorporated by reference herein.

Supply tube 36 is, at least in part, disposed within a lumen 38 ofneedle 26, with the supply tube extending distally from a proximal end40 of the needle toward a distal end 42. The exemplary supply tube 36comprises a fused silica tubular structure (not illustrated) having apolymer coating and extending in cantilever into the needle lumen 38.Supply tube 36 may have an inner lumen with an effective inner diameterof less than about 200 μm, the inner diameter often being less thanabout 100 μm, and typically being less than about 70 μm. Exemplaryembodiments of supply tube 36 have inner lumens of between about 15 and70 μm, such as about 30 μm or 65 μm. An outer diameter or size of supplytube 36 will typically be less than about 1000 μm, often being less thanabout 800 μm, with exemplary embodiments being between about 60 and 150μm, such as about 90 μm or 105 μm. The tolerance of the inner lumendiameter of supply tubing 36 will preferably be relatively tight,typically being about +/−10 μm or tighter, often being +/−5 μm ortighter, and ideally being +/−3 μm or tighter (e.g., +/−1 μm), as thesmall diameter supply tube may provide the majority of (or evensubstantially all of) the metering of the cooling fluid flow into needle26. Additional details on various aspects of needle 26 along withalternative embodiments and principles of operation are disclosed ingreater detail in U.S. Pat. No. 9,254,162 entitled “Dermal andTransdermal Cryogenic Microprobe Systems and Methods,” the entirecontents of which are incorporated herein by reference. Previouslyincorporated U.S. Pat. No. 8,409,185 also discloses additional detailson the needle 26 along with various alternative embodiments andprinciples of operation.

The cooling fluid injected into lumen 38 of needle 26 will typicallycomprise liquid, though some gas may also be injected. At least some ofthe liquid vaporizes within needle 26, and the enthalpy of vaporizationcools the needle and also the surrounding tissue engaged by the needle.An optional heater 44 (illustrated in FIG. 1B) may be used to heat theproximal region of the needle in order to prevent unwanted skin damagein this area, as discussed in greater detail below. Controlling apressure of the gas/liquid mixture within needle 26 substantiallycontrols the temperature within lumen 38, and hence the treatmenttemperature range of the tissue. A relatively simple mechanical pressurerelief valve 46 may be used to control the pressure within the lumen ofthe needle, with the exemplary valve comprising a valve body such as aball bearing, urged against a valve seat by a biasing spring. Anexemplary relief valve is disclosed in U.S. Provisional PatentApplication No. 61/116,050 previously incorporated herein by reference.Thus, the relief valve may allow better temperature control in theneedle, minimizing transient temperatures. Further details on exhaustvolume are disclosed in previously incorporated U.S. Pat. No. 8,409,185.

The heater 44 may be thermally coupled to a thermally responsive element50, which is supplied with power by the controller 22 and thermallycoupled to a proximal portion of the needle 26. The thermally responsiveelement 50 can be a block constructed from a material of high thermalconductivity and low heat capacity, such as aluminum. A firsttemperature sensor 52 (e.g., thermistor, resistance temperaturedetectors, or thermocouple) can also be thermally coupled the thermallyresponsive element 50 and communicatively coupled to the controller 22.A second temperature sensor 53 can also be positioned near the heater44, for example, such that the first temperature sensor 52 and secondtemperature sensor 53 are placed in different positions within thethermally responsive element 50. In some embodiments, the secondtemperature sensor 53 is placed closer to a tissue contacting surfacethan the first temperature sensor 52 is placed in order to providecomparative data (e.g., temperature differential) between the sensors52, 53. The controller 22 can be configured to receive temperatureinformation of the thermally responsive element 50 via the temperaturesensor 52 in order to provide the heater 44 with enough power tomaintain the thermally responsive element 50 at a particulartemperature.

The controller 22 can be further configured to monitor power draw fromthe heater 44 in order to characterize tissue type, perform devicediagnostics, and/or provide feedback for a tissue treatment algorithm.This can be advantageous over monitoring temperature alone, since powerdraw from the heater 44 can vary greatly while temperature of thethermally responsive element 50 remains relatively stable. For example,during treatment of target tissue, maintaining the thermally responsiveelement 50 at 40° C. during a cooling cycle may take 1.0 W initially(for a needle <10 mm in length) and is normally expected to climb to 1.5W after 20 seconds, due to the needle 26 drawing in surrounding heat. Anindication that the heater is drawing 2.0 W after 20 seconds to maintain40° C. can indicate that an aspect of the system 10 is malfunctioningand/or that the needle 26 is incorrectly positioned. Correlations withpower draw and correlated device and/or tissue conditions can bedetermined experimentally to determine acceptable treatment powerranges.

In some embodiments, it may be preferable to limit frozen tissue that isnot at the treatment temperature, i.e., to limit the size of a formedcooling zone within tissue. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature profile or temperature volume gradientrequired to therapeutically affect the tissue therein. To achieve this,metering coolant flow could maintain a large thermal gradient at itsoutside edges. This may be particularly advantageous in applications forcreating an array of connected cooling zones (i.e., fence) in atreatment zone, as time would be provided for the treatment zone tofully develop within the fenced in portion of the tissue, while theouter boundaries maintained a relatively large thermal gradient due tothe repeated application and removal of refrigeration power. This couldprovide a mechanism within the body of tissue to thermally regulate thetreatment zone and could provide increased ability to modulate thetreatment zone at a prescribed distance from the surface of the skin. Arelated treatment algorithm could be predefined, or it could be inresponse to feedback from the tissue.

Such feedback could be temperature measurements from the needle 26, orthe temperature of the surface of the skin could be measured. However,in many cases monitoring temperature at the needle 26 is impractical dueto size constraints. To overcome this, operating performance of thesensorless needle 26 can be interpolated by measuring characteristics ofthermally-coupled elements, such as the thermally responsive element 50.

Additional methods of monitoring cooling and maintaining an unfrozenportion of the needle include the addition of a heating element and/ormonitoring element into the needle itself. This could consist of a smallthermistor or thermocouple, and a wire that could provide resistiveheat. Other power sources could also be applied such as infrared light,radiofrequency heat, and ultrasound. These systems could also be appliedtogether dependent upon the control of the treatment zone desired.

Alternative methods to inhibit excessively low transient temperatures atthe beginning of a refrigeration cycle might be employed instead of ortogether with the limiting of the exhaust volume. For example, thesupply valve 32 might be cycled on and off, typically by controller 22,with a timing sequence that would limit the cooling fluid flowing sothat only vaporized gas reached the needle lumen 38 (or a sufficientlylimited amount of liquid to avoid excessive dropping of the needle lumentemperature). This cycling might be ended once the exhaust volumepressure was sufficient so that the refrigeration temperature would bewithin desired limits during steady state flow. Analytical models thatmay be used to estimate cooling flows are described in greater detail inpreviously incorporated U.S. Pat. No. 9,254,162.

FIG. 2B shows a cross-section of the housing 16. This embodiment of thehousing 16 may be powered by an external source, hence the attachedcable, but could alternatively include a portable power source. Asshown, the housing includes a cartridge holder 50. The cartridge holder50 includes a cartridge receiver 52, which may be configured to hold apressured refrigerant cartridge 18. The cartridge receiver 52 includesan elongated cylindrical passage 70, which is dimensioned to hold acommercially available cooling fluid cartridge 18. A distal portion ofthe cartridge receiver 52 includes a filter device 56, which has anelongated conical shape. In some embodiments, the cartridge holder 50may be largely integrated into the housing 16 as shown, however, inalternative embodiments, the cartridge holder 50 is a wholly separateassembly, which may be pre-provided with a coolant fluid source 18.

The filter device 56 may fluidly couple the coolant fluid source(cartridge) 18 at a proximal end to the valve 32 at a distal end. Thefilter device 56 may include at least one particulate filter 58. In theshown embodiment, a particulate filter 58 at each proximal and distalend of the filter device 56 may be included. The particulate filter 58can be configured to prevent particles of a certain size from passingthrough. For example, the particulate filter 58 can be constructed as amicroscreen having a plurality of passages less than 2 microns in width,and thus particles greater than 2 microns would not be able to pass.

The filter device 56 also includes a molecular filter 60 that isconfigured to capture fluid impurities. In some embodiments, themolecular filter 60 is a plurality of filter media (e.g., pellets,powder, particles) configured to trap molecules of a certain size. Forexample, the filter media can comprise molecular sieves having poresranging from 1-20 Å. In another example, the pores have an average sizeof 5 Å. The molecular filter 60 can have two modalities. In a firstmode, the molecular filter 60 will filter fluid impurities received fromthe cartridge 18. However, in another mode, the molecular filter 60 cancapture impurities within the valve 32 and fluid supply tube 36 when thesystem 10 is not in use, i.e., when the cartridge 18 is not fluidlyconnected to the valve 32.

Alternatively, the filter device 56 can be constructed primarily fromePTFE (such as a Gore-Tex® material), sintered polyethylene (such asmade by POREX), or metal mesh. The pore size and filter thickness can beoptimized to minimize pressure drop while capturing the majority ofcontaminants. These various materials can be treated to make ithydrophobic (e.g., by a plasma treatment) and/or oleophobic so as torepel water or hydrocarbon contaminants.

It has been found that in some instances fluid impurities may leach outfrom various aspects of the system 10. These impurities can includetrapped moisture in the form of water molecules and chemical gasses. Thepresence of these impurities is believed to hamper cooling performanceof the system 10. The filter device 56 can act as a desiccant thatattracts and traps moisture within the system 10, as well as chemicalsout gassed from various aspects of the system 10. Alternately thevarious aspects of the system 10 can be coated or plated withimpermeable materials such as a metal.

As shown in FIG. 2B and in more detail in FIG. 2C and FIG. 2D, thecartridge 18 can be held by the cartridge receiver 52 such that thecartridge 18 remains intact and unpunctured. In this inactive mode, thecartridge may not be fluidly connected to the valve 32. A removablecartridge cover 62 can be attached to the cartridge receiver 52 suchthat the inactive mode is maintained while the cartridge is held by thesystem 10.

In use, the cartridge cover 62 can be removed and supplied with acartridge containing a cooling fluid. The cartridge cover 62 can then bereattached to the cartridge receiver 52 by turning the cartridge cover62 until female threads 64 of the cartridge cover 62 engage with malethreads of the cartridge receiver 52. The cartridge cover 62 can beturned until resilient force is felt from an elastic seal 66, as shownin FIG. 2C. To place the system 10 into use, the cartridge cover 62 canbe further turned until the distal tip of the cartridge 18 is puncturedby a puncture pin connector 68, as shown in FIG. 2D. Once the cartridge18 is punctured, cooling fluid may escape the cartridge by flowingthrough the filter device 56, where the impurities within the coolingfluid may be captured. The purified cooling fluid then passes to thevalve 32, and onto the coolant supply tube 36 to cool the probe 26. Insome embodiments the filter device, or portions thereof, may bereplaceable.

In some embodiments, the puncture pin connector 68 can have a two-wayvalve (e.g., ball/seat and spring) that is closed unless connected tothe cartridge. Alternately, pressure can be used to open the valve. Thevalve closes when the cartridge is removed. In some embodiments, theremay be a relief valve piloted by a spring which is balanced byhigh-pressure nitrous when the cartridge is installed and the system ispressurized, but allows the high-pressure cryogen to vent when thecryogen is removed. In addition, the design can include a vent port thatvents cold cryogen away from the cartridge port. Cold venting cryogenlocally can cause condensation in the form of liquid water to form fromthe surrounding environment. Liquid water or water vapor entering thesystem can hamper the cryogenic performance. Further, fluid carryingportions of the cartridge receiver 52 can be treated (e.g., plasmatreatment) to become hydrophobic and/or oleophobic so as to repel wateror hydrocarbon contaminants.

Turning now to FIG. 3A and FIG. 3B, an exemplary embodiment of probe 300having multiple needles 302 is described. In FIG. 3A, probe housing 316includes threads 306 that allow the probe to be threadably engaged withthe housing 16 of a cryogenic device. O-rings 308 fluidly seal the probehousing 316 with the device housing 16 and prevent coolant from leakingaround the interface between the two components. Probe 300 includes anarray of three distally extending needle shafts 302, each having asharpened, tissue penetrating tip 304. In certain embodiments, usingthree linearly arranged needles allows a greater area of tissue to betreated as compared with a single needle. In use, coolant flows throughlumens 310 into the needle shafts 302 thereby cooling the needle shafts302. Ideally, only the distal portion of the needle shaft 302 would becooled so that only the target tissue receives the cryogenic treatment.However, as the cooling fluid flows through the probe 300, probetemperature decreases proximally along the length of the needle shafts302 towards the probe hub 318. The proximal portion of needle shaft 302and the probe hub 318 contact skin and may become very cold (e.g. −20°C. to −25° C.) and this can damage the skin in the form of blistering orloss of skin pigmentation. Therefore it would be desirable to ensurethat the proximal portion of needle shaft 302 and hub 318 remains warmerthan the distal portion of needle shaft 302. A proposed solution to thischallenge is to include a heater element 314 that can heat the proximalportion of needle shaft 302 and an optional temperature sensor 312 tomonitor temperature in this region. To further this, a proximal portionof the needle shaft 302 can be coated with a highly thermally conductivematerial, e.g., gold, that is conductively coupled to both the needleshaft 302 and heater element 314. Details of this construction aredisclosed below.

In the exemplary embodiment of FIG. 3A, heater element 314 is disposednear the needle hub 318 and near a proximal region of needle shaft 302.The effective resistance of the heater element is preferably 1Ω to 1K Ω,and more preferably from 3Ω to 50Ω. Additionally, a temperature sensor312 such as a thermistor or thermocouple is also disposed in the samevicinity. Thus, during a treatment as the needles cool down, the heater314 may be turned on in order to heat the hub 318 and proximal region ofneedle shaft 302, thereby preventing this portion of the device fromcooling down as much as the remainder of the needle shaft 302. Thetemperature sensor 312 may provide feedback to controller 22 and afeedback loop can be used to control the heater 314. The cooling powerof the nitrous oxide may eventually overcome the effects of the heater,therefore the microprocessor may also be programmed with a warning lightand/or an automatic shutoff time to stop the cooling treatment beforeskin damage occurs. An added benefit of using such a heater element isthe fact that the heat helps to moderate the flow of cooling fluid intothe needle shaft 302 helping to provide more uniform coolant mass flowto the needles shaft 302 with more uniform cooling resulting.

The embodiment of FIG. 3A illustrates a heater fixed to the probe hub.In other embodiments, the heater may float, thereby ensuring proper skincontact and proper heat transfer to the skin. Examples of floatingheaters are disclosed in commonly assigned Int'l Pub. No. WO 2010/075448entitled “Skin Protection for Subdermal Cryogenic Remodeling forCosmetic and Other Treatments,” the entirety of which is incorporated byreference herein.

In this exemplary embodiment, three needles are illustrated. One ofskill in the art will appreciate that a single needle may be used, aswell as two, four, five, six, or more needles may be used. When aplurality of needles are used, they may be arranged in any number ofpatterns. For example, a single linear array may be used, or a twodimensional or three dimensional array may be used. Examples of twodimensional arrays include any number of rows and columns of needles(e.g. a rectangular array, a square array, elliptical, circular,triangular, etc.), and examples of three dimensional arrays includethose where the needle tips are at different distances from the probehub, such as in an inverted pyramid shape.

FIG. 3B illustrates a cross-section of the needle shaft 302 of needleprobe 300. The needle shaft can be conductively coupled (e.g., welded,conductively bonded, press fit) to a conductive heater 314 to enableheat transfer therebetween. The needle shaft 302 is generally a small(e.g., 20-30 gauge) closed tip hollow needle, which can be between about0.2 mm and 15 cm, preferably having a length from about 0.3 cm to about10 cm. The conductive heater element 314 can be housed within aconductive block 315 of high thermally conductive material, such asaluminum and include an electrically insulated coating, such as Type IIIanodized coating to electrically insulate it without diminishing itsheat transfer properties. The conductive block 315 can be heated by aresistor or other heating element (e.g. cartridge heater, nichrome wire,semiconductor device, etc.) bonded thereto with a heat conductiveadhesive, such as epoxy. A thermistor can be coupled to the conductiveblock 315 with heat-conductive epoxy or other thermally conductive meansto allow for temperature monitoring. Other temperature sensors may alsobe used, such as a thermocouple or resistance temperature detectors.

An optional cladding 320 of conductive material may be conductivelycoupled to the proximal portion of the shaft of the needle 302, whichcan be stainless steel. In some embodiments, the cladding 320 is a layerof gold, or alloys thereof, coated on the exterior of the proximalportion of the needle shaft 302. In some embodiments, the exposed lengthof cladding 320 on the proximal portion of the needle is 2-100 mm. Insome embodiments, the cladding 320 can be of a thickness such that theclad portion has a diameter ranging from 0.017-0.020 in., and in someembodiments 0.0182 in. Accordingly, the cladding 320 can be conductivelycoupled to the material of the needle 302, which can be less conductive,than the cladding 320. The cladding 320 may modify the lateral forcerequired to deflect or bend the needle 26. Cladding 320 may be used toprovide a stiffer needle shaft along the proximal end in order to moreeasily transfer force to the leading tip during placement and allow thedistal portion of the needle to deflect more easily when it isdissecting a tissue interface within the body. The stiffness of needle26 can vary from one end to the other end by other means such asmaterial selection, metal tempering, variation of the inner diameter ofthe needle 26, or segments of needle shaft joined together end-to-end toform one contiguous needle 26. In some embodiments, increasing thestiffness of the distal portion of the needle 26 can be used to flex theproximal portion of the needle to access difficult treatment sites as inthe case of upper limb spasticity where bending of the needle outsidethe body may be used to access a target peripheral nerve along thedesired tissue plane.

In some embodiments, the cladding 320 can include sub-coatings (e.g.,nickel) that promote adhesion of an outer coating that would otherwisenot bond well to the needle shaft 302. Other highly conductive materialscan be used as well, such as copper, silver, aluminum, and alloysthereof. In some embodiments, a protective polymer or metal coating cancover the cladding to promote biocompatibility of an otherwisenon-biocompatible but highly conductive cladding material. Such abiocompatible coating however, would be applied to not disruptconductivity between the conductive block 315. In some embodiments, aninsulating layer, such as a ceramic material, is coated over thecladding 320, which remains conductively coupled to the needle shaft302.

In use, the cladding 320 can transfer heat to the proximal portion ofthe needle 302 to prevent directly surrounding tissue from dropping tocryogenic temperatures. Protection can be derived from heating thenon-targeting tissue during a cooling procedure, and in some embodimentsbefore the procedure as well. The mechanism of protection may beproviding heat to pressurized cryogenic cooling fluid passing within theproximal portion of the needle to affect complete vaporization of thefluid. Thus, the non-target tissue in contact with the proximal portionof the needle shaft 302 does not need to supply heat, as opposed totarget tissue in contact with the distal region of the needle shaft 302.To help further this effect, in some embodiments the cladding 320 iscoating within the interior of the distal portion of the needle, with orwithout an exterior cladding. To additionally help further this effect,in some embodiments, the distal portion of the needle can be thermallyisolated from the proximal portion by a junction, such as a ceramicjunction. While in some further embodiments, the entirety of theproximal portion is constructed from a more conductive material than thedistal portion.

In use, it has been determined experimentally that the cladding 320 canhelp limit formation of a cooling zone to the distal portion of theneedle shaft 302, which tends to demarcate at a distal end of thecladding 320. Accordingly, cooling zones are formed only about thedistal portions of the needles. Thus, non-target tissue in directcontact with proximal needle shafts remain protected from effects ofcryogenic temperatures. Such effects can include discoloration andblistering of the skin. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature required to therapeutically affect thetissue therein.

Standard stainless steel needles and gold clad steel needles were testedin porcine muscle and fat. Temperatures were recorded measured 2 mm fromthe proximal end of the needle shafts, about where the cladding distallyterminates, and at the distal tip of the needles. Temperatures for cladneedles were dramatically warmer at the 2 mm point versus the uncladneedles, and did not drop below 4° C. The 2 mm points of the standardstainless steel needles almost equalize in temperature with the distaltip at temperatures below 0° C.

FIGS. 3C and 3D illustrates a detachable probe tip 322 having a hubconnector 324 and an elongated probe 326. The probe tip 322 shares muchof its construction with probe 300. However, the elongated probe 326features a blunt tip 328 that is adapted for blunt dissection of tissue.The blunt tip 328 can feature a full radius tip, less than a full radiustip, or conical tip. In some embodiments, a dulled or truncated needleis used. The elongated probe 326 can be 20 gauge or smaller in diameter,and in some embodiments range in size from 25-30 gauge. As with theembodiments described above, an internal supply tube 330 extends incantilever. However, the exit of the supply tube 330 can be disposed atpositions within the elongated probe 326 other than proximate the blunttip 328. Further, the supply tube 330 can be adapted to create anelongated zone of cooling, e.g., by having multiple exit points forcryofluid to exit from.

The elongated probe 326 and supply tube 330 may be configured toresiliently bend in use, throughout their length at angles approaching120°, with a 5-10 mm bend radius. This may be very challengingconsidering the small sizes of the elongated probe 326 and supply tube330, and also considering that the supply tube 330 is often constructedfrom fused silica. Accordingly, the elongated probe 326 can beconstructed from a resilient material, such as stainless steel, and of aparticular diameter and wall thickness [0.004 to 1.0 mm], such that theelongated probe in combination with the supply tube 330 is not overlyresilient so as to overtly resist manipulation, but sufficiently strongso as to prevent kinking that can result in coolant escaping. Forexample, the elongated probe can be 15 gauge or smaller in diameter,even ranging from 20-30 gauge in diameter. The elongated probe can havea very disparate length to diameter ratio, for example, the elongatedprobe can be greater than 30 mm in length, and in some cases range from30-150 mm in length (e.g., 90 mm length). To further the aforementionedgoals, the supply tube 330 can include a polymer coating 332, such as apolyimide coating that terminates approximately halfway down its length,to resist kinking and aid in resiliency. The polymer coating 332 can bea secondary coating over a primary polyimide coating that extends fullyalong the supply tube. However, it should be understood that the coatingis not limited to polyimide, and other suitable materials can be used.In some embodiments, the flexibility of the elongated probe 326 willvary from the proximal end to the distal end. For example, by creatingcertain portions that have more or less flexibility than others. Thismay be done, for example, by modifying wall thickness, adding material(such as the cladding discussed above), and/or heat treating certainportions of the elongated probe 326 and/or supply tube 330. For example,decreasing the flexibility of elongated probe 326 along the proximal endcan improve the transfer of force from the hand piece to the elongatedprobe end for better feel and easier tip placement for treatment. Theelongated probe and supply line 330 are may be configured to resilientlybend in use to different degrees along the length at angles approaching120°, with a varying bend radius as small as 5 mm. In some embodiments,the elongated probe 326 will have external markings along the needleshaft indicating the length of needle inserted into the tissue.

FIG. 3E illustrates an exemplary detachable probe tip 322 insertedthrough skin surface SS. As illustrated, the probe tip 322 is insertedalong an insertion axis IA through the skin surface SS. Thereafter, theneedle may be bent away from the insertion axis IA and advanced toward atarget tissue TT in order to position blunt tip 328 adjacent to thetarget tissue TT. In some embodiments, the target tissue may be theinfrapatellar branch of the saphenous nerve. In other embodiments thetarget tissue may be one or more branches of the anterior femoralcutaneous nerve or the lateral femoral cutaneous nerve.

In some embodiments, the probe tip 322 does not include a heatingelement, such as the heater described with reference to probe 300, sincethe effective treating portion of the elongated probe 326 (i.e., thearea of the elongated probe where a cooling zone emanates from) is welllaterally displaced from the hub connector 324 and elongated probeproximal junction. Embodiments of the supply tube are further describedbelow and within commonly assigned U.S. Pub. No. 2012/0089211, which isincorporated by reference.

FIGS. 4A-4B illustrate a distal end of an exemplary cryoprobe 800 fortreating a nerve according to some embodiments. The probe 800 may have aneedle 805 extending distally that is configured to generate a cryozone(defined by the 0° C. isotherm) 810. In some embodiments, as illustratedin the close up of needle 805 in FIG. 4B, the needle 805 may include oneor more marks along the length of the needle. The one or more marks maycomprise a mark 815 for marking a distal end of the cryozone 810 that isgenerated by the probe 800, a mark 820 for marking a proximal end of thecryozone 810 that is generated by the probe 800, and/or a mark 825 formarking a center of a the cryozone 810 that is generated by the probe800.

The marks 815, 820, 825 may be utilized for visually aligning the needle805 of a probe 800 with a target nerve. For example, FIG. 5A illustratesan exemplary method 900 of treating a nerve according to someembodiments. At step 902, a needle of the cryotherapy probe ispositioned across the target nerve. The one or more markings indicativeof a treatment area (e.g., marks 815, 820, 825) of the needle may bealigned with the nerve 904. After alignment, the cryotherapy probe maybe activated to deliver the cooling therapy 906.

In some embodiments, the needle may be provided with an echogeniccoating that makes the needle more visible under ultrasound imaging. Forexample, in some embodiments, the entire length of the needle may beprovided with an echogenic coating. Alternatively, the one or more ofthe marks 815, 820, 825, may be provided with an echogenic coating suchthat the distal end, proximal end, or center of the cryozone associatedwith the needle is visible under ultrasound imaging. In otherembodiments, the one or more marks may be provided by a lack ofechogenic coating. For example, in some embodiments, the length of theneedle may be provided with an echogenic coating except for at the oneor more marks 815, 820, 825, such that when viewed under ultrasoundguidance, the distal, proximal, or center of the cryozone would beassociated with the portion of the needle without the echogenic coating.Alternatively, the length of the needle may be provided with theechogenic coating that ceases at the center of the associated cryozone,such that when viewed under ultrasound guidance, the distal end of theechogenic coating would be associated with a center of a cryozone of theneedle.

Long needles may be used in some embodiments (e.g., 8-15 mm, 20 mm, 90mm etc.). Longer needles may require a smaller gauge (larger diameter)needle so they have sufficient rigidity for improved control whilepositioning of the distal end deep in the tissue, but not so large as tocreate significant mechanical injury to the skin and tissue wheninserted (e.g., greater diameter than 20 G). Alternate configurations ofthe device may have two or more needles spaced generally 2-5 mm apart oflengths ranging from up to 20 mm or greater, typically of 27 gauge, 25gauge or 23 gauge. Single needle configurations may be even longer(e.g., 90 mm) for reaching target tissues that are even deeper(e.g., >15 mm or so below the dermis). Longer needle devices (e.g., >10mm) may not need active heating of the skin warmer and/or cladding foundin designs using shorter needle(s), as the cooling zone may be placedsufficiently deep below the dermis to prevent injury. In someembodiments, devices with single long needle configurations may benefitfrom active nerve location such as ultrasound or electrical nervestimulation to guide placement of the needle. Further, larger targetsmay require treatment from both sides to make sure that the cold zonecreated by the needle fully covers the target. Adjacent treatmentsplacing the needle to either side of a nerve during two successivetreatment cycles may still provide an effective treatment of the entirenerve cross-section.

In some situations, a probe with multiple spaced apart needles may bepreferable (e.g., 2, 3, 4 or more). A device employing multiple needlesmay decrease the total treatment duration by creating larger coolingzones. Further, a multi-needle device may be configured to providecontinuous cooling zones between the spaced apart needles. In someembodiments, the needles may be spaced apart by 1-5 mm. The spacing maybe dependent on the type of tissue being targeted. For example, whentargeting a nerve, it may be preferable to position the nerve betweenthe two or more needles so that cooling zones are generated on bothsides of the nerve. Treating the nerve from both sides may increase theprobability that the entire cross-section of the nerve will be treated.For superficial peripheral nerves, the nerves may be at depths rangingfrom 2-6 mm and may be smaller in diameter, typically <2 mm.Accordingly, devices for treating superficial peripheral nerves maycomprise two or more 27 gauge needles spaced <2 mm apart and havingtypical lengths less than 7 mm (e.g., 6.9 mm); however longer needlesmay be required to treat the full patient population in order to accesspatients with altered nerve anatomy or patients with higher amounts ofsubcutaneous tissue such as those with high BMIs.

A treatment cycle may comprise a 10 second pre-warm phase, followed by a60 second cooling phase, followed thereafter by a 15 second post-warmphase with 40° C. skin warmer throughout. It should be understood thatother treatment cycles may be implemented. In some embodiments, apre-warming cycle can range from 0 to up to 30 seconds, preferably 5-15seconds sufficient to pre-warm the cryoprobe and opposing skin.Treatment cooling may range from 5-120 seconds, preferably 15-60 secondsbased on the flow rate, geometry of the cryoprobe, size of the therapyzone, size of the target nerve or tissue and the mechanism of actiondesired. Post-warming can range from 0-120 seconds, preferably less than60 seconds, more preferably 10-15 seconds sufficient to return thecryoprobe to a steady state thermal condition and possibly to free thecryoprobe needle(s) from the frozen therapy zone (e.g., at least 0° C.)prior to removing the cryoprobe needles. For example, in someembodiments, devices with 6.9 mm long cladded needles may be warmed witha 30° C. heater. The treatment cycle may comprise a 10 second pre-warmphase, a 35 second cooling phase, and a 15 second post-warm phase.Advantageously, such a treatment cycle may make an equivalent cryozoneas the treatment cycle used in the study in a shorter amount of time(e.g., a 35 second cooling phase compared to a 60 second cooling phase).

In some embodiments, treatment devices and treatment cycles may beconfigured to deliver a preferred cryozone volume. For example, in someembodiments, devices and treatment cycles may be configured to generatecryozones having a cross-sectional area of approximately 14-55 mm2(e.g., 27 mm2). Optionally, the devices and treatment cycles may beconfigured to generate cryozones having a volume of approximately 65-125mm3 (e.g., 85 mm3).

Accordingly, in some embodiments, treatment cycles may be configuredwith cooling phases ranging between 15-75 seconds (e.g., 30 seconds, 35seconds, 40 seconds, 45 seconds, etc.) depending on cooling fluid flowrates, warming phase durations, warming phase temperature, number ofcooling needles, needle spacing, or the like in order to generate adesired cryozone. Similarly, treatment cycles may be configured withwarming phases operating a temperatures ranging between 10-45° C.depending on the length of cooling phases, number of needles, needlespacing, etc., in order to generate a desired cryozone. In someembodiments the temperature can be set to one temperature during thepre-warm phase, another temperature during the cooling phase, and athird temperature during the post-warm phase.

In some embodiments, devices may be configured to limit flow rate of acooling fluid to approximately 0.25-2.0 SLPM, preferably 0.34-1.0 SLPM(gas phase). Optionally, in some embodiments, it may be preferable toconfigure the device and the treatment cycle to maintain the tip at lessthan −55° C. during cooling phases. In some embodiments, it may bepreferable to configure the device and the treatment cycle to have thetip return to at least 0° C. at the end of the post-warm phase so as toensure the device may be safely removed from the tissue after thetreatment cycle.

While generally describing treatment cycles as includingpre-heating/warming phases, it should be understood that other treatmentcycles may not require a pre-heating/warming phase. For example, largerneedle devices (e.g., 30-90 mm) may not require a pre-heat/warm phase.Larger needles may rely on the body's natural heat to bring the needleto a desired temperature prior to a cooling phase.

In some embodiments of the present invention, treatment guidance canrely on rigid or boney landmarks because they are less dependent uponnatural variations in body size or type, e.g. BMI. Soft tissues,vasculature and peripheral nerves pass adjacent to the rigid landmarksbecause they require protection and support. The target nerve to relievepain can be identified based on the diagnosis along with patientsidentifying the area of pain, biomechanical movements that evoke painfrom specific areas, palpation, and diagnostic nerve blocks using atemporary analgesic (e.g. 1-2% Lidocaine). Target nerve (tissue) can belocated by relying on anatomical landmarks to indicate the anatomicalarea through which the target nerve (tissue) reside. Alternatively,nerve or tissue locating technologies can be used. In the case ofperipheral nerves, electrical stimulation or ultrasound can be used tolocate target nerves for treatment. Electrical nerve stimulation canidentify the nerve upon stimulation and either innervated muscle twitchin the case of a motor nerve or altered sensation in a specific area inthe case of a sensory nerve. Ultrasound is used to visualize the nerveand structures closely associated with the nerve (e.g. vessels) toassist in placing the cryoprobe in close proximity to the target nerve.By positioning the patient's skeletal structure in a predeterminedposition (e.g. knee bent 30 degrees or fully extended), one can reliablyposition the bones, ligaments, cartilage, muscle, soft tissues(including fascia), vasculature, and peripheral nerves. Externalpalpation can then be used to locate the skeletal structure and therebylocate the pathway and relative depth of a peripheral nerve targeted fortreatment.

A treatment of peripheral nerve tissue to at least −20° C. for greaterthan 10 seconds (e.g., at least 20 seconds preferably) may be sufficientto trigger 2nd degree Wallerian degeneration of the axon and myelinatedsheath. Conduction along the nerve fibers is stopped immediatelyfollowing treatment. This provides immediate feedback as to the locationof the target peripheral nerve or associated branches when theassociated motion or sensation is modified. This can be used to refinerigid landmark guidance of future treatments or to determine whetheraddition treatment is warranted.

By using rigid landmarks, one may be able to direct the treatmentpattern to specific anatomical sites where the peripheral nerve islocated with the highest likelihood. Feedback from the patientimmediately after each treatment may verify the location of the targetperipheral nerve and its associated branches. Thus, it should beunderstood that in some embodiments, the use of an electrical nervestimulation device to discover nerve location is not needed or used,since well-developed treatment zones can locate target nerves. This maybe advantageous, due the cost and complexity of electrical nervestimulation devices, which are also not always readily available.

In alternative embodiments of the invention, one could use an electricalnerve stimulation device (either transcutaneous or percutaneous) tostimulate the target peripheral nerve and its branches. Withtranscutaneous electrical nerve stimulation (TENS), the pathway of thenerve branch can be mapped in XY-coordinates coincident with the skinsurface. The Z-coordinate corresponding to depth normal to the skinsurface can be inferred by the sensitivity setting of the electricalstimulation unit. For example, a setting of 3.25 mA and pulse durationof 0.1 ms may reliably stimulate the frontal branch of the temporalnerve when it is within 7 mm of the skin surface. If a higher currentsetting or longer pulse duration is required to stimulate the nerve,then the depth may be >7 mm. A percutaneous electrical nerve stimulator(PENS) can also be used to locate a target peripheral nerve. Based onrigid anatomical landmarks, a PENS needle can be introduced through thedermis and advanced into the soft tissues. Periodic stimulating pulsesat a rate of 1-3 Hz may be used to stimulate nerves within a knowndistance from the PENS needle. When the target nerve is stimulated, thesensitivity of the PENS can be reduced (e.g., lowering the currentsetting or pulse duration), narrowing the range of stimulation. When thenerve is stimulated again, now within a smaller distance, the PENSsensitivity can be reduced further until the nerve stimulation distanceis within the therapy zone dimensions. At this point, the PENS needlecan be replaced with the cryoneurolysis needle(s) and a treatment can bedelivered. The PENS and cryoneurolysis needles can be introduced bythemselves or through a second larger gage needle or cannula. This mayprovide a rigid and reproducible path when introducing a needle and whenreplacing one needle instrument with another. A rigid pathway may guidethe needle to the same location by preventing needle tip deflection,which could lead to a misplaced therapy and lack of efficacy.

While many of the examples disclosed herein relate to puncturing theskin in a transverse manner to arrive at a target nerve, othertechniques can be used to guide a device to a target nerve. For example,insertion of devices can be made parallel to the surface of the skin,such that the (blunted) tip of the device glides along a particularfascia to arrive at a target sensory nerve. Such techniques and devicesare disclosed in U.S. Pub. No. 2012/0089211, the entirety of which isincorporated by reference. Possible advantages may include a singleinsertion site and guidance of a blunt tip along a layer common with thepath or depth of the target nerve. This technique may be aposition-treatment-thaw, reposition-treatment-thaw, etc.

In further aspects of the present invention, a cryoneurolysis treatmentdevice may be provided that is adapted to couple with or be fullyintegrated with a nerve stimulation device such that nerve stimulationand cryoneurolysis may be performed concurrently with thecryo-stimulation device. Accordingly, embodiments of the presentdisclosure may improve nerve targeting during cryoneurolysis procedures.Improvements in nerve localization and targeting may increase treatmentaccuracy and physician confidence in needle placement during treatment.In turn, such improvements may decrease overall treatment times, thenumber of repeat treatments, and the re-treatment rate. Further,additional improvements in nerve localization and targeting may reducethe number of applied treatment cycles and may also reduce the number ofcartridge changes (when replaceable refrigerant cartridges are used).Thus, embodiments of the present disclosure may provide one or moreadvantages for cryoneurolysis by improving localization and treatment oftarget nerves. Hence, some aspects of the present disclosure providemethods, devices, and systems for localizing and targeting a nerveduring cryoneurolysis procedures.

FIG. 5B illustrates one such method 500 of locating and treating a nerveaccording to some embodiments. At step 502, a transcutaneous electricalstimulation (TENS) device and/or anatomical landmarks may be used topre-locate a target nerve or otherwise generally locate a target nervelocation. At step 504, one or more needles of an integrated cooling andstimulation device may be inserted into the tissue. At step 506,percutaneous nerve localization may be conducted to determine 507whether the one or more needles is proximal to the target nerve. If thenerve localization using percutaneous nerve stimulation 506 isunsuccessful, the one or more needles may be repositioned 508 within thetissue. Thereafter, percutaneous nerve localization 506 may be conductedagain to determine whether the repositioning successfully places the oneor more needles sufficiently proximal to the target nerve. If the nervelocalization using percutaneous nerve stimulation is successful uponinsertion 504 or after repositioning 508, cryoneurolysis may then bedelivered 509 using one or more needles of the treatment device.

The method 500 may be used for cosmetic and/or other medical treatments(e.g., pain alleviation or the like). In some cosmetic applications, atarget nerve may be between 3-7 mm in depth, for example. In othermedical applications, a target nerve may be upwards of 50 mm in depth ordeeper. It may be beneficial to locate the target nerve to within 2 mmfor at least some of treatments. Additionally, in some applications, itmay be beneficial to be able to locate and differentiate motor nervesfrom sensory nerves. For example, in some cosmetic applications thattarget motor nerves for wrinkle alleviation, it may be advantageous tolocate and avoid treating sensory nerves to limit side effects due tothe cosmetic procedure. For example, method 500 may be used to targetthe temporal branch of the facial nerve (TBFN). Additional nervestreated with method 500 in and around the face may include theauriculotemporal nerve. The nerves may run above the SDTF layer. Thedepth of the SDTF layer varies along treatment lines and amongindividuals and as such the target nerve depth may also vary frompatient to patient. Accordingly, an integrated stimulation and coolingtreatment device may be beneficial in such a procedure. In an additionalnon-limiting example, method 500 may be used to target the infrapatellarbranch of the saphenous nerve (ISN). The ISN is a sensory nerve thatinnervates the anterior aspect of the knee. Cryoneurolysis of the ISNmay alleviate pain experienced in the knee of a patient (e.g., due toosteoarthritis or the like). While anatomical features may be used togenerally localize a treatment box for the target nerve, a plurality oftreatments may be needed before the target nerve is treated within thebox. Accordingly, an integrated nerve stimulation and cooling treatmentdevice may provide more accurate treatments and may thereby limit thenumber of treatments required for treatment and reduce a treatment time.Additional treatments that may benefit from such a device include, butare not limited to: head pain, knee pain, plantar fasciitis, back pain,tendonitis, shoulder pain, movement disorders, intercostal pain,pre-surgical pain, post-herpetic neuralgia, post-surgical pain, phantomlimb pain, etc. Associated nerves include: greater occipital nerve,lesser occipital nerve, trigeminal nerves, suprascapular nerve,intercostal nerves, brachialis nerve, superficial radial nerve,ilioinguinal nerve, iliohypogastric nerve, anterior femoral cutaneousnerve, lateral femoral cutaneous nerve, infrapatellar branch of thesaphenous nerve, common peroneal nerve branches, tibial nerve branches,superficial peroneal nerve, sural nerve.

Electrical nerve stimulation localizes nerves by transmission ofelectrical pulses. The electrical impulses in turn excite nerves byinducing a flow of ions through the neuronal cell membrane(depolarization), which results in an action potential that maypropagate bi-directionally. The nerve membrane depolarization may resultin either muscle contraction or paresthesia, depending on the type ofnerve fiber (motor vs. sensory). The current density a nerve reacts toor “sees” decreases with distance from the nerve:

$I = {k\left( \frac{i}{r^{2}} \right)}$

where k is a constant that depends on electrode size, pulse width,tissue impedance, nerve fiber size, etc.; i is the current delivered;and r is the distance from the nerve. This corresponds to higherthreshold currents at a distance from the nerve.

In some embodiments, an insulated needle having a small conducting oruninsulated portion may have minimal current threshold when the needleis on the nerve. Non-insulated needles in contrast may transmit currentthrough the entire length and may have a lower current density along thetreatment portion of the needle. As such, non-insulated needles mayrequire more current than insulated needles at the same distance fromthe nerve and may have less discrimination of distances as the needleapproaches the nerve. Accordingly, while not essential, in someembodiments, cryo-stimulation devices may be provided that include aninsulated nerve stimulation needle.

In some embodiments, the integrated cooling and stimulation needle probemay have a single needle for both cooling and nerve stimulation. Forexample, FIG. 6A illustrates an exemplary needle assembly 510 having asingle needle 512 that may be used to perform the method 500 accordingto some embodiments of the disclosure. FIG. 6B illustrates a close upview of the needle 512 of the exemplary needle assembly 510 of FIG. 6Aaccording to some embodiments. In use, coolant may flow through theneedle 512 (e.g. via cooling fluid supply tube or the like) therebycooling a distal end of the needle 512 and producing a cold zone 521associated with the needle 512. The needle 512 may have a cooling center522 along the length of the needle 512 that is associated with a centerof the cold zone 521 produced by the needle 512. Additionally, theneedle 512 may be constructed from an electrically conductive materialand may also have an electrically insulated coating 523 disposed about alength of the needle 512. The electrically insulated coating 523 mayelectrically insulate a proximal portion of a length of the needle 512that is adjacent the distal end of the housing 514 and may extend towarda distal portion of the length of the needle 512. The electricallyinsulated coating 523 may be a fluoropolymer coating, a silicone rubbercoating, a parylene coating, a ceramic coating, an epoxy coating, apolyimide coating, or the like. A proximal end of needle 512 may beuninsulated and may be configured to couple with an electrical nervestimulation generator 524 of a percutaneous electrical stimulationdevice. A distal end of needle 512 may be uninsulated such that anelectric field 526 (FIG. 6B) generated by electrical nerve stimulationgenerator 524 happens about the distal end of needle 512. In someembodiments, the distal end of the electrically insulated coating 523may be at the cooling center 522 of the needle 512. In such embodiments,the intensity of the electric field 526 produced by electrical nervestimulation generator 524 may be co-incident with the center of the coldzone 521 that is produced by the needle 512, as illustrated in FIG. 6B.

In some embodiments the coating 523 may be 0.001 inches thick.Optionally, coating 523 may be applied by masking off the cooling center522 of needle 512 and then coating the needle 512 with the electricallyinsulating material 523. Additionally, while needle assembly 510 isillustrated with a needle 512 without insulation at the distal end ofthe needle 512, it should be understood that this is exemplary. In someembodiments of the present disclosure, the distal end of needle 512 mayhave a coating of the electrically insulating material 523, asillustrated in FIG. 6C, while the portion of the needle 512 associatedwith the center of the cold zone 521 remains uninsulated.

As mentioned above, a proximal end of needle 512 may be uninsulated andmay be configured to couple with an electrical nerve stimulationgenerator 524. In some embodiments, the electrical nerve stimulationgenerator 524 may have an input that is configured to couple with acorresponding electrical port of the treatment device. For example, FIG.7 illustrates an exemplary treatment device 600. The treatment device600 includes a handle 610 that is configured to be coupled with areplaceable needle assembly 612. The handle 610 may further include areplaceable refrigerant cartridge 614. The cartridge 614 may be securedto handle 610 by a cartridge cap 616. The cartridge 614 and thecartridge cap 616 may be housed by distal cover 618. Optionally, aneedle assembly cover 620 may be provided to house the needle assembly612 when the device 600 is not in use.

In some embodiments, the input electrical port configured to receive aninput from the electrical nerve stimulation generator 524 may beprovided on the replaceable needle assembly 612. For example, asillustrated in FIG. 8 illustrates an exemplary needle assembly 612 withan input electrical port 622. The input electrical port 622 isconfigured to couple with electrical nerve stimulation generator 524 toelectrically couple the electrical nerve stimulation generator 524 withthe uninsulated proximal portion of one or more electrical stimulationneedles 623 of device 600.

Additionally, in some embodiments, the input electrical port configuredto receive an input from the electrical nerve stimulation generator 524may be provided on the handle 610 in addition to or in the alternativeto the electrical port 622 on needle assembly 612. For example, asillustrated in FIG. 9, a proximal end of handle 610 may includeelectrical port 624 for receiving an input from the electrical nervestimulation generator 524. FIG. 10 illustrates a close up view of theproximal end of housing 610. As can be seen, the distal end of housing610 may include a status light 626 for the cartridge status, a statuslight 628 for the needle assembly, a device serial number 630, and/or areset access 632 in addition to electrical port 624. The one or moreinput electrical ports 622, 624 may be configured to be electricallycoupled with one or more of the electrical stimulation needles of thedevice 600.

Optionally, in some embodiments, the electrical nerve stimulationgenerator 524 may be fully integrated with the treatment device. Forexample, FIG. 11 illustrates yet another exemplary treatment system 634with a fully integrated electrical nerve stimulation generator 524. Thesystem 634 includes a housing 636 that defines a handle of the device.An electrical adapter 638 may be disposed at the distal end of housing636 that is configured to electrically couple with a replaceable needleassembly (not shown). Housing 636 may house electrical nerve stimulationgenerator 524. Electrical nerve stimulation generator 524 mayelectrically couple with the adapter 638. Adapter 638 may provide aninterface between the electrical nerve stimulation generator 524 and areplaceable needle assembly when the needle assembly is coupled withadapter 638.

While the exemplary needle assembly 510 of FIG. 6A is illustrated with asingle needle for performing the cooling treatment in addition to thenerve stimulation, it should be understood that other treatment devicesor needle assemblies may be provided with a plurality of needles. One ofskill in the art will appreciate that two, three, four, five, six, ormore needles may be used. When a plurality of needles are used, they maybe arranged in any number of patterns. For example, a single lineararray may be used, or a two dimensional or three dimensional array maybe used. Examples of two dimensional arrays include any number of rowsand columns of needles (e.g. a rectangular array, a square array,elliptical, circular, triangular, etc.), and examples of threedimensional arrays include those where the needle tips are at differentdistances from the probe hub, such as in an inverted pyramid shape.Accordingly, in some embodiments, the integrated cooling and stimulationneedle probe may have a plurality of needles for cooling and/or nervestimulation. For example, FIG. 12 illustrates an exemplary needleassembly 710 that includes a plurality of needles 712 that may performthe method 500 with a plurality of needles according to some embodimentsof the disclosure. In use, coolant may flow through one or more of theneedles 712 thereby cooling a distal end of the one or more needles 712and producing a cold zone 721 associated with the needle assembly 710.The needle assembly 710 may have a cooling center 722 that is associatedwith a center of the cold zone 721 produced by the one or more needles712. Additionally, at least one of the needles 712 (in the illustratedembodiment, center needle 712 c) may be constructed from an electricallyconductive material and may also have an electrically insulated coating723 disposed about a length of the needle 712 c. The electricallyinsulated coating 723 may electrically insulate a proximal portion of alength of the needle 712 c that is adjacent the distal end of thehousing 714 and may extend toward a distal portion of the length of theneedle 712 c. The electrically insulated coating 723 may be afluoropolymer coating, a silicone rubber coating, a parylene coating, aceramic coating, an epoxy coating, a polyimide coating or the like. Aproximal end of needle 712 c may be uninsulated and may be configured tocouple with the electrical nerve stimulation generator 524 of apercutaneous electrical stimulation device, e.g., through a mannerdescribed above, such as an electrical port on the needle assemblyhousing, an electrical port on the treatment device housing, anintegrated generator 524 that electrically couples to needle 712 c viaan adapter between the device handle and the needle assembly 710 or thelike. The portion of needle 712 c that is disposed at the cooling center722 may be uninsulated such that the intensity of the electric fieldproduced by electrical nerve stimulation generator 524 via needle 712 cmay be co-incident with the center of the cold zone 721 that is producedby the needle assembly 710.

While illustrated as including three needles 712, it should beunderstood that this is exemplary and non-limiting. Two, four, five ormore needles may be provided in other embodiments. Further, whileillustrated with each of the needles 712 being supplied by a coolingfluid supply tube and thus each of the needles 712 being configured tocool to produce cold zone 721, in other embodiments, only some of theplurality of needles may be configured to provide the cooling treatment.Other needles 712 may be provided separately for electrical stimulation.Accordingly, in some embodiments, center needle 712 may be provided forelectrical stimulation only, while the adjacent needles 712 may beprovided to produce cold zone 721. Put in another way, in someembodiments, stimulation needle (e.g., needle 712 c) may not include acold center along the length of the needle, but nevertheless, thecooling center 722 of the cold zone 721 associated with the needleassembly 710 may be disposed along the length of the stimulation needle.Thus, the stimulation needle may provide more accurate targeting of atarget nerve with the cold zone 721 whether or not it provides coolingitself.

Additionally, it should be understood that while assembly 710 isillustrated with a single stimulating needle 712 c, additional needles712 of assembly 710 may be configured to separately stimulate asdesired. Accordingly, some or all of the plurality of needles 712 may beconfigured to provide nerve stimulation. Thus, nerve stimulationgenerator 524 may be electrically coupled with each stimulating needle.

Further, in some embodiments, an adjacent needle (e.g., needles 712adjacent to 712 c) may provide an electrical return during nervestimulation. Accordingly, one or more of the adjacent needles may beconstructed from a conductive material and may be uninsulated at alocation proximate to an uninsulated portion of an adjacent nervestimulation needle. Optionally, adjacent needles may also include anelectrically insulated coating that extends from a proximal portion ofthe needle adjacent to the housing toward a distal portion of theneedle.

In still further embodiments, during cryoneurolysis delivery 509, nervestimulation may be conducted to provide feedback to the treatment. Forexample, in some embodiments, nerve stimulation may be performedcontinuously and/or concurrently with cryoneurolysis delivery 509 todetermine the efficacy of the treatment in real time. Optionally, thenerve stimulation may be repeated in a discrete intervals duringcryoneurolysis delivery 509. In such embodiments, cryoneurolysisdelivery 509 may continue until there is a cessation of motor functionor paresthesia. In some embodiments, cryoneurolysis delivery 509 may beshorter in duration when the nerve stimulation feedback is associatedwith a successful treatment. In other embodiments, cryoneurolysisdelivery 509 may be longer in duration when the nerve stimulationfeedback indicates that the nerve has not been successfully treated.Further, initial tests surprisingly suggest that ice ball formation bythe treatment needles of the assembly may be produced at a quicker ratewhen the electrical stimulation is concurrently delivered.

In still further embodiments of the present disclosure, a cryoneurolysistreatment device may be provided with an integrated transcutaneouselectrical stimulation device. For example, FIG. 13 illustrates anexemplary treatment system 750 with an integrated transcutaneouselectrical stimulation probe 752 according to some embodiments. FIG. 14illustrates an exemplary operation of the system 750 of FIG. 13according to some embodiments. Treatment system 750 further includes twocooling treatment needles 754 for insertion through the tissue surface756 to produce a cooling zone 758 to treat target nerve 760. Thetranscutaneous electrical stimulation probe 752 may have distal end forproviding electrical stimulation through the tissue surface 756 forlocalizing the target nerve 760. A proximal portion of probe 752 may becoupled with a spring 762. After identifying a location of the targetnerve 760, the device 750 may be pressed distally against the tissuesurface 756 to insert needles 754 into the tissue. During needle 754insertion, the spring 762 may compress and the probe 752 may withdrawinto the housing of treatment system 750. Thereafter, the needles 754may deliver cryoneurolysis to produce cold zone 758. Such an embodimentmay localize a target nerve transcutaneously and may allow the treatmentneedles to be inserted into the tissue without having to firstinterchange the transcutaneous electrical stimulation device for thedevice with the cooling treatment needles.

FIGS. 15A-18 illustrate yet further aspects and features of acryoneurolysis treatment device that is adapted to couple with or beintegrated (e.g., partially or fully) with a nerve stimulation deviceaccording to certain embodiments described herein. Such cold therapytreatment devices may include one or more features, in whole or in part,of any of the embodiments described herein. Both nerve stimulation andcryoneurolysis may be performed or delivered by such a cryo-stimulationdevice. For example, nerve stimulation and cryoneurolysis may bedelivered concurrently or alternately with the cryo-stimulation device.Further, in some embodiments, the device may be operated by a singleoperator or clinician. Accordingly, such embodiments of the presentdisclosure may improve nerve targeting during cryoneurolysis procedures.Improvements in nerve localization and targeting may increase treatmentaccuracy and physician confidence in needle placement during treatment.In turn, such improvements may decrease overall treatment times, thenumber of repeat treatments, and the re-treatment rate. Further,additional improvements in nerve localization and targeting may reducethe number of needle insertions, applied treatment cycles, and may alsoreduce the number of cartridge changes (when replaceable refrigerantcartridges are used). Thus, embodiments of the present disclosure mayprovide one or more advantages for cryoneurolysis treatments byimproving localization and treatment of target nerves. Hence, someaspects of the present disclosure provide methods, devices, and systemsfor localizing, targeting, and treating a nerve with integrated coldtherapy and electrical stimulation systems.

An integrated cooling and stimulation needle probe may have a singleneedle for both cooling and nerve stimulation. For example, FIG. 15Aillustrates an exemplary needle probe or assembly 910 having one or moreneedles 912 extending distally from a housing 914 that may be used todeliver nerve stimulation for localization of the nerve and cold therapyfor treatment of the nerve (e.g., the method 500 as described above)according to some embodiments of the present disclosure. Such needles912 may be configured to deliver bipolar, monopolar, or alternatebetween bipolar and monopolar electrical stimulation for localizingtarget nerves for cold therapy treatment. In use, coolant may flowthrough the needle 912 (e.g. via cooling fluid supply tube or the like)thereby cooling a distal portion of the needle 912 and producing a coldzone 921 associated with the needle 912. The needle 912 may also have acooling center, as described above with respect to FIGS. 6A-6C and 12(not shown in FIG. 15A) along the length of the needle 912 that isassociated with a center of the cold zone 921 produced by the needle912. As described in more detail below, in some embodiments, cold zone921 or cooling center may be located between at least one pair ofelectrodes (e.g., electrical conductors, contacts, poles, exposedconducting portions) identified individually as electrode 944 andelectrode 946 on needle 912.

The needle 912 may be constructed from an electrically conductivematerial and may also have an electrically insulated coating 923disposed about a length of the needle 912. The electrically insulatedcoating 923 may electrically insulate selected or desired portions ofthe needle 912. For example, coating 923 may insulate a proximal portionof a length of the needle 912 that is adjacent the distal end of theprobe or needle assembly housing 914 and may extend toward a distalportion of the length of the needle 912. The electrically insulatedcoating 923 may be made from a dielectric or other suitable type ofinsulating material. For example, the coating 923 may be a fluoropolymercoating, a silicone rubber coating, a parylene coating, a ceramiccoating, an epoxy coating, a polyimide coating or the like.

One or more regions or portions of the needle 912 may be uninsulated bythe coating 923 (e.g., exposed or conductive). For example, a proximalend of needle 512 may be uninsulated and may be configured to couplewith an electrical nerve stimulation generator 924 of a percutaneous ortranscutaneous electrical stimulation device. The electrical nervestimulation generator 924 may be integrated with (e.g., positioned on orwithin) housing 914. In other embodiments, the electrical nervestimulation generator 924 may be positioned away from housing 914. Forexample, housing 914 or needle assembly 910 may have a port configuredto be coupled to an electrical nerve stimulation generator (e.g., an offthe shelf generator). In certain embodiments, a first portion at adistal end of needle 912 and a second portion proximate the firstportion may be uninsulated with a third insulated portion extendingtherebetween (FIG. 15A). The electrodes 946 and 944 may be positioned atthe uninsulated first and second portions, respectively. In someembodiments, only the first portion or the second portion isuninsulated. In other embodiments, electrodes 946 and/or 944 may beconductive portions of the needle 912 that are uninsulated or exposed bythe coating 923. For example, a distal part of needle 912 (e.g., tip)may be made from electrically conductive material exposed or uninsulatedby coating 923. The electrodes 946 and 944 may form a pair of electrodeselectrically coupled to electrical nerve stimulation generator 924 fordelivering bipolar electrical stimulation to locate target nerves. Usingbipolar electrical stimulation may provide improved control over astimulation region (e.g., size and shape of the region), which mayresult in improved predictability of location of or proximity to a nerverelative to monopolar electrical stimulation, where the return electrodeof a larger surface is located relatively far away from the activeelectrode. The electrodes or contacts for bipolar stimulation aregenerally positioned closer together relative to monopolarconfigurations. Thus, in some embodiments, electric field distribution(and hence the range of the stimulation region) may be significantlycontrolled by controlling the geometry of each electrode, therebyresulting in improved predictability of the proximity to a target nervefor bipolar electrical stimulation configurations.

The pair of electrodes 946 and 944 may be a cathode and anode,respectively. In other embodiments, electrode 946 is an anode andelectrode 944 is a cathode. An electric field 940 is generated byelectrical nerve stimulation generator 924 about the pair of electrodes946, 944. As illustrated in FIG. 15A, electric field strength (depictedby concentration of electric field lines 941) and hence current densityare generally highest between the pair of electrodes. As such, a loweststimulation-current threshold (e.g., minimum current to achieve nervestimulation) may be detected between the pair of electrodes. Therefore,in certain embodiments, a coldest point in the needle 912 (e.g., coolingzone 921 or the center of cooling zone 921) may be located between thepair of electrodes (e.g., third insulated portion extendingtherebetween) to deliver cryoneurolysis treatment to a localized nerve(e.g., current threshold corresponding to a desired distance from thetarget nerve is achieved).

While the exemplary needle assembly 910 of FIG. 15A and others hereinare illustrated with a single needle for performing the coolingtreatment in addition to the nerve stimulation, it should be understoodthat other treatment devices or needle assemblies may be provided with aplurality of needles (e.g., as described in more detail above withrespect to needle assemblies 510 and 710). One of skill in the art willappreciate that two, three, four, five, six, or more needles may be usedand may be arranged in any number of patterns. Accordingly, in someembodiments, the integrated cooling and stimulation needle assembly 910may have a plurality of needles for cooling, nerve stimulation, or both.In some embodiments, two or more needles of a needle assembly may flanka target nerve. In certain embodiments, one or more needles extendingparallel to the first needle include one of the pair of electrodes(e.g., electrode 944, 946) for bipolar or monopolar stimulation. In someembodiments, one or more needles of the needle assembly provide theelectrical return for a stimulation circuit.

In some embodiments, while bipolar electrical stimulation may facilitateimproved precision for localizing a nerve, it may be beneficial toswitch or alternate between bipolar and monopolar modes of electricalstimulation as illustrated in FIG. 15B. For example, monopolarelectrical stimulation may be delivered to localize a target nervewithin a first distance (e.g., about 10 mm) and then switched to bipolarelectrical stimulation to further localize a target nerve within asecond distance less than the first distance (e.g., of about 0.5 mm). Inthis manner, bipolar electrical stimulation may be delivered to further“fine-tune” localization of the nerve after initial monopolar electricalstimulation is delivered to localize the nerve within the firstdistance.

As illustrated in FIG. 15B, the needle 912 may include a pair ofelectrodes (identified individually as 946 and 944) as in the embodimentof FIG. 15A, configured to deliver bipolar electrical stimulation. Theneedle 912 may include a cooling zone, conductive portions, andinsulative coating 923 with exposed or uninsulated portions as describedabove. Further, the pair of electrodes may also be electrically coupledto the electrical nerve stimulation generator 924 for bipolar,monopolar, or both bipolar and monopolar electrical stimulation. Forexample, an insulated wire 943 a (dashed lines to illustrate returnpaths) may electrically connect return electrode 944 to the generator924 and a separate insulated wire 943 b (solid line to illustrate activepaths) may electrically connect active electrode 946 to the generator924 only during bipolar stimulation. It will be appreciated, that wire943 b may electrically connect electrode 946 to the generator 924 duringboth monopolar and/or bipolar stimulation and that one or more wires(e.g., wire 943) may be included in any of the embodiments describedherein to connect electrodes to an electrical stimulation generator.

As further illustrated in FIG. 15B, a third electrode 947 configured asa return electrode may be positioned on a skin 948 of a patient (e.g.,spaced apart or away from the needle 912). In some embodiments, thethird electrode may be a patch electrode such as a silver to silverchloride patch. In other embodiments, the third electrode (e.g., areturn electrode) may be positioned on or within the housing 914, aneedle heater block or component (e.g., as described in more detailbelow with respect to FIG. 18), or on or within the electrical nervestimulation generator 924. In certain embodiments, the housing, heaterblock or component, or nerve stimulation generator itself acts as thethird electrode or return. The third electrode 947 is arranged with atleast one (e.g., an active electrode) of the pair of electrodes (e.g.,electrode 946) and electrically coupled to the electrical nervestimulation generator 924 via wire 943 a for a return pathway to providemonopolar electrical stimulation for nerve localization. The thirdelectrode 947 may have a substantially larger surface area than theactive electrode to better disperse current for reducing or minimizingheat generation from monopolar electrical stimulation. An electric field942 is generated by electrical nerve stimulation generator 924 betweenthe active electrode 946 and the third electrode 947 via monopolarstimulation for localizing a target nerve (e.g., within a firstdistance). As described above, electrical stimulation may be alternatedor switched between monopolar (for generation of electric field 942) andbipolar stimulation (for generation of focused electric field 940) asdesired to localize a target nerve according to embodiments of thepresent disclosure.

Needle 912 may include any suitable tip configuration. For example,needle 912 may include a substantially symmetrical pyramid orwedge-shaped tip configuration as illustrated in FIG. 15A or anasymmetrical beveled edge as illustrated in FIG. 15B. The pair ofelectrodes 946, 944 may be positioned in a substantially symmetricalconfiguration as illustrated in FIG. 15A. In other embodiments, the pairof electrodes 946, 944 may have an asymmetrical configuration asillustrated in FIG. 15B and described in more detail below with respectto FIGS. 16A-16D.

FIGS. 16A-16D illustrate various embodiments of the pair of electrodes946, 944 with asymmetrical electrode configurations that can be providedwith needle probe or assembly 910. For example, needle shape, electrodetype, size (e.g., contact surface area), shape (e.g., concave, convex),orientation, location, and/or electrical properties (e.g., capacitance,conductivity) may be varied to provide asymmetrical electrodeconfigurations as described herein. FIG. 16A illustrates an asymmetricalelectrode configuration where electrode 944 (e.g., the anode or returnelectrode) is located on needle 912 as described above. For example, acenter of electrode 944 may be aligned with a longitudinal axis ofneedle 912. However, electrode 946 (e.g., the cathode or activeelectrode) is located asymmetrically relative to electrode 944 via anasymmetrical needle tip configuration (e.g., a beveled edge). In theembodiment of FIG. 16A, electrode 946 may positioned only at a tip ofneedle 912 that has an asymmetrical tip configuration (e.g., a bevelededge) rather than a pyramid-shaped symmetrical tip as illustrated inFIG. 15A. For example, the electrically conductive needle 912 mayinclude insulative coating 923 as described above with respect to FIG.15A. A tip of the beveled distal edge of needle 912 may be exposed fromthe insulative coating 923 such that a conductive portion (e.g.,electrode 946) is exposed at the tip. In such embodiments, electricfield 940 is generated with a stimulating region sufficient for nervelocalization oriented only on one side of the needle 912 (e.g., whereelectric field strength is highest) as depicted by the concentration ofelectric field lines 941 on a right side of the needle 912 in FIG. 16A.In such embodiments, a target nerve would be preferentially stimulatedif it was positioned on the right side of the needle 912 with thestimulator 924 generating a minimum current threshold.

FIG. 16B illustrates another asymmetrical electrode configurationaccording to another embodiment of the present disclosure. The pair ofelectrodes 944, 946 are located on the needle 912 in an asymmetricalconfiguration. As described in more detail above with respect to FIG.15A, the needle 912 may have an insulative coating 923. The pair ofelectrodes may be positioned at uninsulated or exposed portions of theneedle 912. In some embodiments, one or more of the pair of electrodesmay be conducting portions of the needle 912 exposed or uninsulated bythe coating 923. For example, electrode 946 may be an exposed distalbeveled edge of needle 912 as opposed to only the tip as described abovewith respect to the embodiment of FIG. 16A. Electrode 944 may be anexposed shaft portion of needle 912 located proximally relative to andelectrically isolated from electrode 946 (e.g., a dielectric or otherinsulative material between the two electrodes within the needle 912 toprevent them from shorting together within the needle). Electrode 944may extend along a side portion of the needle 912 such that a center ofthe electrode 944 is spaced apart from a longitudinal axis of needle912. Electrode 946 may be coupled with the electrical nerve stimulationgenerator 924 with an insulated wire 943 b as described above.

Electric field 940 is generated with a stimulating region oriented onone side of the needle 912 (e.g., where electric field strength ishighest) as depicted by the concentration of electric field lines 941only one a left side of the needle 912 in FIG. 16B. In such embodiments,a right side of electrode 944 may be insulated with the insulativecoating 923. Asymmetrically configuring the pair of electrodes mayprovide directionality as a stimulating region is oriented only on oneside of the needle 912. Such directionality may facilitate or provide abinary searching or localizing methodology (e.g., by determining whichside of the needle 912 a nerve resides on with each placement or needleinsertion) with minimal or reducing needle insertions and withdrawalsaccordingly. Implementing an asymmetrical electrode design orconfiguration on a single rotatable needle 912 (e.g., rotatable afterinsertion into a patient or electrode orientation may be rotated withoutwithdrawal from a patient), allows identification of a direction (e.g.,X-Y-Z position) of the nerve with respect to the coldest point in theneedle 912 (e.g., cooling zone 921 or the center of cooling zone 921).For example, X and Y directions may be identified by with electricalstimulation and rotation of the needle 912 to determine correspondingdistance in each direction. Z direction may be identified by insertiondepth of the needle 912.

FIG. 16C illustrates another asymmetrical electrode configurationaccording to yet another embodiment of the present disclosure. It may beadvantageous in certain embodiments to provide a pair of electrodes 944,946 on the needle 912 with substantially different contact surfaceareas. For example, contact surface area ratio of the electrodes mayrange between about 2 to 1 to about 8 to 1. In other embodiments, theratio is about 4 to 1. A minimum current threshold for electricalstimulation with such electrodes generally occurs near the electrodewith the substantially smaller or smallest area. In some embodiments, acurrent threshold near electrode 946 is about 2, 3, 4, or 5 times thecurrent threshold near electrode 944 or vice versa. This may provideonly a single or one stimulating region configured to achieve adistinguished minimum current threshold to localize a target nerve(e.g., where electric field strength and current density are highest asdepicted by the concentration of electric field lines 941).

For example, electrode 944 may have a substantially larger surface arearelative to electrode 946 located along a beveled distal edge of needle912. Concentrated electric field lines 941 and hence current density arehighest near the electrode 946 with substantially smaller surface arearelative to electrode 944. This may provide one stimulating regionconfigured to achieve a distinguished minimum current threshold tolocalize the target nerve (e.g., proximate electrode 946 on a left sideof needle 912). As described above with respect to FIG. 15A, a cold zonemay be delivered between the electrodes 944, 946. Providing onestimulating region (e.g., at or near a distal end of the needle 912) mayallow a user or clinician to more precisely or accurately position theneedle 912 and accordingly, the cold zone relative to a target nerve fortreatment. For example, knowing a position of a cold zone relative tothe distal edge electrode 946 (e.g., above the one stimulating region),a user or clinician may evaluate whether a cold zone of needle 912 hasbeen inserted past a target zone of the cold zone with respect to atarget nerve after the target nerve has been localized.

FIG. 16D illustrates another asymmetrical electrode configurationaccording to a further embodiment of the present disclosure. In someembodiments, it may be desirable to increase or expand a stimulatingregion by effectively spreading out generated electric field 940. Forexample, in certain embodiments, too small of a stimulating regionbetween electrodes may lead to too much current effectively “shorting”between electrodes (e.g., electrodes 944, 946) during stimulation.Reducing the current that is effectively shorting between the electrodesby increasing total current delivery may inadvertently stimulateun-targeted neuromuscular tissue. Therefore, in some embodiments,increasing a stimulating region may be provided by reducing orminimizing a conductive-fluid region between a pair of electrodes (e.g.,electrodes 944, 946). This may be achieved by facing one or both of theelectrodes away from each other (e.g., oriented or facing opposingdirections) and/or by using concave-shaped electrodes (e.g., as electricfield lines are perpendicular to a surface of an electrode). Asillustrated in FIG. 16C, electrode 946 can extend along a beveled edgetip of needle 912 and face substantially in a first direction. Electrode944 can extend along a side of the needle 912 such that it faces asecond direction substantially opposite the first direction. In thismanner, electric field 940 is generated and extends or spreadseffectively from one side of needle 912 to an opposing second side ofneedle 912. A stimulating region may be spread or expanded accordingly.

Any of the asymmetrical electrode configurations of FIGS. 16A-16D may beapplied to any of the needle assembly embodiments described herein.Further two or more configurations may be provided or included asdesired. As described above, alternating or switching between monopolarand bipolar stimulation may also be provided with such embodiments.Additionally, needle assemblies may be provided with a single needle ormultiple needles to delivery stimulation and/or cold therapy. In someembodiments, a needle assembly comprises two needles or more needles. Insome embodiments, one needle carries an anode electrode and anotherneedle carries a cathode electrode for bipolar stimulation. In otherembodiments, a second and/or third needle flanking a first needleprovides the return to the first needle during electrical stimulation ofa target nerve. It will be appreciated that the active and returnelectrodes may be selectable by the user or by the processor of thedevice. For example, the selection for the return may be based on whichneedle is closest to the nerve. Likewise, two flanking needles could beselected as the active needles (e.g., double cathode) with the centerneedle serving as the return needle (e.g., anode).

As described above in more detail with respect to certain embodiments,integrated cold therapy and electrical stimulation systems may providedherein. Such cryo-stimulation devices may include a housing (e.g.,housing 914) that defines a handle of the device. Housing 914 may housean electrical nerve stimulation generator 924. Electrical nervestimulation generator 924 may electrically coupled with a needleassembly (e.g., needle assembly 910) to generate a stimulation signal(e.g., stimulation region, electric field). The stimulation signal maybe generated within the cryo-stimulation device. Alternatively, in orderto maintain the stimulator generator 924 as a device separate from thecryo-stimulation housing, a stimulation signal may be received from anoff-the-shelf generator (e.g., PENS (input)) connected to thecryo-stimulation device via, for example, a port as described in moredetail above.

FIGS. 17A-17C illustrate exemplary needle probes or assemblies 1810having one or more split needles 1812 (identified individually as 1812a, 1812 b, and 1812 c) that may also be used to deliver nervestimulation for localization and targeting of the nerve and cold therapyfor treatment of the nerve (e.g., the method 500 as described above)according to some embodiments of the present disclosure. The splitneedles 1812 may include electrodes configured for bipolar and/ormonopolar stimulation as described above. The split needles 1812 mayinclude symmetrically and/or asymmetrically configured electrodes. Thesplit needles 1812 may be electrically coupled with an electrical nervestimulation generator 1824. The electrical nerve stimulation generator1824 may be integrated with (e.g., positioned on or within) a housing1814 of the needle assemblies. In other embodiments, the electricalnerve stimulation generator 1824 may be positioned away from housing1814. For example, the housing 1814 or needle assemblies may have a portconfigured to be coupled to an electrical nerve stimulation generator(e.g., an off-the-shelf PENS generator).

FIG. 17A illustrates a split needle 1812 a having a first shaft 1872 anda second shaft 1870 extending along (e.g., contiguously) the first shaft1872. In some embodiments, first shaft 1872 and second shaft 1870 sharea boundary or edge. In other embodiments, the first shaft 1872 includesa first edge extending along a second edge of second shaft 1870. Whileillustrated with the first shaft 1872 on a left side of second shaft1870, in other embodiments, first shaft 1872 extends along a right sideof second shaft 1870. In some embodiments, forming a needle forcryo-stimulation treatments with two shafts rather than a singledintegrated shaft may decrease manufacturing costs or improvemanufacturability.

The first shaft 1872 may be a conductive shaft configured to deliverelectrical stimulation (e.g., from a tip portion) from electricalstimulation generator 1824 to localize a target nerve. In someembodiments, the first shaft 1872 is constructed from an electricallyconductive material. The first shaft 1872 may include an insulativecoating 1823 as described above with respect to other embodiments. Incertain embodiments, the first shaft 1872 is insulated along its length(e.g., length of needle 1812 inserted into a patient). A small portionor area 1874 (e.g., region, tip, edge) at a distal end portion may beconductive (e.g., exposed or uninsulated) and configured to contact atarget nerve or be positioned proximate to the target nerve forlocalizing the target nerve. In the illustrated embodiment, conductiveportion 1874 a (e.g., surrounding in broken lines) is a portion of thetip of the beveled edge of the needle 1812 a. In other embodiments,conductive portion 1874 may include a region or area at the end of a tipof the needle (e.g., conductive portion 1874 b as illustrated in FIG.17B in hatching). In other embodiments, first shaft 1872 may includepairs of electrodes as described above. Further, in some embodiments,first shaft 1872 may retract relative to second shaft 1870. For example,first shaft 1872 may be retracted or removed from a patient when notbeing used (e.g., after localization of a target nerve and/or duringcold therapy). Retraction of the first shaft 1872 may provide improvednerve encapsulation by a cooling zone or cooling center (e.g., ice ball)of the second shaft 1870 as described in more detail below.

Distal ends of the first and second shafts may be aligned to form asubstantially continuous distal tip of needle 1812 (e.g., an asymmetricbeveled edge (FIGS. 17A-17B), a symmetric pyramid tip (FIG. 17C)).Second shaft 1870 may be configured to delivery cold therapy to a targetnerve. Second shaft 1870 may include a distal end and a proximal end anda length extending therebetween. Second shaft 1870 includes a lumen 1838(e.g., a blind shaft) and a supply tube 1836 disposed at least in partin the lumen 1838. The supply tube 1836 extends distally from a proximalend of the needle 1812 toward a distal end. The exemplary supply tube1836 comprises a fused silica tubular structure (not illustrated) havinga polymer coating, as described previously. A cooling fluid source asdescribed in more detail above may be coupled to the supply tube 1836 todirect cooling fluid flow into a lumen 1834 of the tube 1836 so thatliquid from the cooling fluid flow vaporizes within the lumen 1834 toproduce a cold zone (e.g., to treat a targeted nerve) with a coolingcenter which may enable ice ball formation at a target nerve.

FIG. 17C illustrates a split needle 1812 c having three shafts. A firstshaft 1872 sandwiched between a second shaft 1870 a and a third shaft1870 b extending along (e.g., contiguously) opposing sides or edges ofthe first shaft 1872. Distal ends of the shafts may be aligned to form asubstantially continuous distal tip of needle 1812 c. For example, thethree shafts may form a pyramid tip as illustrated in FIG. 17C. In otherembodiments, the three shafts may be aligned to form a beveled edge. Aconductive region may extend along the distal tip (e.g., as identifiedin broken lines) or include a larger region as illustrated in FIG. 17B.The shafts 1870 a and 1870 b may be configured as shaft 1870 describedabove to provide cold therapy to a target nerve. Spacing of shafts 1870a and 1870 b may be optimized such that liquid from the cooling fluidflow that vaporizes within the lumens 1834 to produce cold zones (e.g.,to treat a targeted nerve) may enable wider and/or flatter ice ballformation at a target nerve. A wider, flatter ice ball may potentiallyallow large nerves or larger bundles of nerves to be treated faster. Insome embodiments, such larger nerves may be treated with only a singletreatment. Additionally, the needle 1812 c may allow improved targetingand/or treatment of the nerve when shaft 1872 is retracted to allow atarget nerve to be flanked by the two outer shafts 1870 a and 1870 b andtheir respective cooling zones or centers (e.g., ice balls).

FIG. 18 illustrates an exemplary embodiment of integrated cold therapyand electrical stimulation cryo-stimulation devices with integratedreturn of the electrical signal. A needle assembly 1910 includes one ormore needles 1912 configured to provide both electrical stimulation andcold therapy. The needle assembly 1910 may include a housing 1914 and anelectrical stimulation generator 1924 coupled to the needle 1912. Thegenerator 1924 may be integrated within the housing 1914 or positionedaway from the housing 1914 as described in more detail above withrespect to other embodiments of the present disclosure. The needleassembly 1910 is configured to localize and treat a target nerve 1984after insertion through skin 1982 of a patient. The needle assembly 1910may include a heater assembly 1944 which includes associated componentssuch as a heater block or other thermally responsive element and/orsensors. The heater may heat skin proximal near an insertion region toprevent or reduce unwanted skin damage in the area.

An electrical signal may be generated by the stimulation generator 1924and travel in a loop as illustrated by the arrows. The signal may travelthrough the skin (e.g., skin and adipose tissue) of a patient tostimulate and localize the target nerve 1984. In some embodiments, theelectrical signal may return through in the heater assembly orcomponents 1944 attached to the heater. The heater components (e.g.,heater block) 1944 may be kept in contact with skin of the patientduring electrical stimulation. In alternative embodiments, theelectrical circuit or signal ground may be integrated or positioned onor within a portion of the housing 1914 or generator 1924. As discussedabove, the needle 1912 may include an insulative coating only exposed ata tip of the needle where the electrical signal is desired (e.g., at ornear the target nerve). For example, a first electrical contact orelectrode may be positioned at the exposed tip of the needle. A secondelectrical contact or electrode (e.g., return electrode) may bepositioned on or within the heater assembly or components 1944 (e.g.,heater block, sensor, housing, generator), or on or within the same ordifferent needle if one or more needles. In other embodiments, otherelectrode or conductor configurations may be provided as discussed inmore detail above. For example, the needle 1912 may include bipolarand/or monopolar electrode configurations. Integrated grounding asdescribed above within the stimulation device may provide improved nervelocalization because electric field strength is increased due to ashorter return distance to ground (e.g., on or within thecryo-stimulation device itself rather than on skin of a patient).Further, integrating the return electrode may also eliminate a need foran additional electrode or contact on the skin of a patient. A furtherbenefit of utilizing the skin-contacting surface of the heater assemblyas the return electrode is that the impedance of this contact asmeasured by the PENS generator can be used to provide feedback to theuser that the skin heater is not in contact with the patient. That is,if the skin warmer is in intimate contact with the patient's skin, thenthe PENS generator will measure a relatively low impedance (e.g., lessthan 10 K ohm, less than 5 K ohm, or less than 1 K ohm), but if the skinheater is not in contact with the patient, then the PENS generator willreport a high-impedance condition. This impedance indication provides anadditional safety benefit for the cryoneurolysis treatment, as itindicates when the heater is not in a position to adequately protect theskin.

One or more computing devices may be adapted to provide desiredfunctionality by accessing software instructions rendered in acomputer-readable form. When software is used, any suitable programming,scripting, or other type of language or combinations of languages may beused to implement the teachings contained herein. However, software neednot be used exclusively, or at all. For example, some embodiments of themethods and systems set forth herein may also be implemented byhard-wired logic or other circuitry, including but not limited toapplication-specific circuits, field programmable gate arrays, or thelike. Combinations of computer-executed software and hard-wired logic orother circuitry may be suitable as well.

Embodiments of the methods disclosed herein may be executed by one ormore suitable computing devices. Such system(s) may comprise one or morecomputing devices adapted to perform one or more embodiments of themethods disclosed herein. As noted above, such devices may access one ormore computer-readable media that embody computer-readable instructionswhich, when executed by at least one computer, cause the at least onecomputer to implement one or more embodiments of the methods of thepresent subject matter. Additionally or alternatively, the computingdevice(s) may comprise circuitry that renders the device(s) operative toimplement one or more of the methods of the present subject matter.

Any suitable computer-readable medium or media may be used to implementor practice the presently-disclosed subject matter, including but notlimited to, diskettes, drives, and other magnetic-based storage media,optical storage media, including disks (e.g., CD-ROMs, DVD-ROMs,variants thereof, etc.), flash memory, RAM, ROM, and other memorydevices, and the like.

The terms “invention,” “the invention,” “this invention” and “thepresent invention” used in this patent are intended to refer broadly toall of the subject matter of this patent and the patent claims below.Statements containing these terms should be understood not to limit thesubject matter described herein or to limit the meaning or scope of thepatent claims below.

The subject matter of embodiments of the present invention is describedhere with specificity, but this description is not necessarily intendedto limit the scope of the claims. The claimed subject matter may beembodied in other ways, may include different elements or steps, and maybe used in conjunction with other existing or future technologies. Thisdescription should not be interpreted as implying any particular orderor arrangement among or between various steps or elements except whenthe order of individual steps or arrangement of elements is explicitlydescribed.

Different arrangements of the components depicted in the drawings ordescribed above, as well as components and steps not shown or describedare possible. Similarly, some features and sub-combinations are usefuland may be employed without reference to other features andsub-combinations. Embodiments of the invention have been described forillustrative and not restrictive purposes, and alternative embodimentswill become apparent to readers of this patent. Accordingly, the presentinvention is not limited to the embodiments described above or depictedin the drawings, and various embodiments and modifications may be madewithout departing from the scope of the claims below.

What is claimed is:
 1. A method of locating and treating a nerve with acryo-stimulation treatment device, the method comprising: releasablycoupling an electrical port on a handle housing or a needle assembly ofa cryo-stimulation treatment device to an external nerve stimulationgenerator; inserting the needle assembly into a tissue of a patient, theneedle assembly having at least one needle having a proximal end, adistal end, and a length therebetween and an electrically insulatedcoating disposed about the length of the needle, the needle configuredto produce a cold zone for focused cold therapy and having a coolingcenter along the length of the needle that is associated with a centerof the cold zone produced by the needle, wherein the needle iselectrically conductive and configured to generate an electrical fieldabout the distal end of the needle for electrically stimulating andlocating a target nerve; electrically stimulating the target nerve withthe needle assembly to localize the target nerve within the tissue,wherein the cooling center associated with the center of the cold zoneis uninsulated such that the electrical field is co-incident with thecenter of the cold zone produced by the needle; after localizing of thetarget nerve, delivering a focused cold therapy to the target nerve withthe needle assembly.
 2. The method of claim 1, further comprising duringdelivery of the focused cold therapy, electrically stimulating thetarget nerve with the needle assembly.
 3. The method of claim 2, furthercomprising sensing an activity of the target nerve during the deliveryof the focused cold therapy for feedback on the delivery of the focusedcold therapy to the target nerve.
 4. The method of claim 1, wherein thetarget nerve comprises intercostal nerves.
 5. The method of claim 4,wherein delivering a focused cold therapy to the intercostal nervesreduces intercostal pain.
 6. The method of claim 1, wherein couplingcomprises electrically coupling an input associated with the nervestimulation generator to the electrical port of the needle assembly. 7.The method of claim 1, wherein coupling comprises electrically couplingan input associated with the nerve stimulation generator to theelectrical port disposed on the handle supporting the needle assembly.8. The method of claim 7, wherein the needle assembly electricallystimulates the target nerve and delivers the focused cold therapy withthe same needle.
 9. The method of claim 8, wherein the needle of theneedle assembly that electrically stimulates the target nerve anddelivers the focused cold therapy comprises a single needle having alength between 5-20 cm.
 10. The method of claim 1, wherein the needleassembly comprises a plurality of needles configured to electricallystimulate the target nerve and deliver the focused cold therapy withdifferent needles of the needle assembly.
 11. The method of claim 1,wherein the needle assembly comprises three needles.
 12. The method ofclaim 11, wherein the needle assembly includes a center needle andneedles adjacent to the center needle, and wherein electricallystimulating the target nerve is performed with the center needle andwherein delivering the focused cold therapy is performed with theneedles adjacent to the center needle.
 13. The method of claim 1,wherein the needle assembly comprises a plurality of needles includingat least a first needle and a second needle adjacent the first needle,and wherein the first needle electrically stimulates the target nerveand wherein the second needle acts as an electrical ground duringelectrical stimulation of the nerve by the first needle.
 14. The methodof claim 1, wherein electrically stimulating the target nerve with theneedle assembly comprises bipolar electrical stimulation via first andsecond electrical contacts of the needle.
 15. The method of claim 1,wherein electrically stimulating the target nerve with the needleassembly comprises monopolar electrical stimulation.
 16. The method ofclaim 1, further comprising releasably coupling the needle assembly tothe handle, and wherein the electrical port electrically couples with anuninsulated portion of the proximal end of the needle and is configuredto receive an input associated with the nerve stimulation generator toelectrically couple the nerve stimulation generator and the needle. 17.The method of claim 1, wherein the electrically insulated coating isdisposed along the proximal end and the distal end of the needle, andwherein the uninsulated cooling center is disposed between the proximalend and the distal end of the needle.
 18. The method of claim 1, whereinthe electrically insulated coating comprises a fluoropolymer, siliconerubber, polyimide, parylene, or epoxy coating.
 19. A method of locatingand treating a nerve, the method comprising: inserting one or moreneedles of a needle assembly into a tissue of a patient; electricallystimulating the nerve with the needle assembly to localize the nervewithin the tissue; after localizing of the nerve, delivering a focusedcold therapy to the nerve with the needle assembly; during delivery ofthe focused cold therapy, electrically stimulating the nerve with theneedle assembly; and sensing an activity of the nerve during thedelivery of the focused cold therapy for feedback on the delivery of thefocused cold therapy to the nerve.
 20. The method of claim 20, whereinthe nerve comprises intercostal nerves and delivering a focused coldtherapy to the intercostal nerves reduces intercostal pain.